Genetics of Genetics of Colorectal Colorectal

CancerCancer

Cancer is a Disease of the Cell CycleCancer is a Disease of the Cell Cycle

ldquoCarcinoma is a genetic disease it is not necessarily inheritedrdquo

Knudsenrsquos ldquotwo hitrdquo hypothesisKnudsenrsquos ldquotwo hitrdquo hypothesis

Types of genes which may mutate Types of genes which may mutate to cause cancerto cause cancer

Oncogenes Suppressor genes DNA repair genes p53

Adenoma-Carcinoma SequenceAdenoma-Carcinoma SequenceAccumulation of MutationsAccumulation of Mutations

DCC MCC p53 K-ras APC MSH2 MLH1 etcDCC MCC p53 K-ras APC MSH2 MLH1 etc

Estimated New Cancer Cases of 10 Estimated New Cancer Cases of 10 Leading Sites by Gender for the US 2000Leading Sites by Gender for the US 2000

MaleProstate 29

Lung and bronchus 14

Colon and rectum 10

Urinary bladder 6

Non-Hodgkinrsquos Lymphoma 5

Melanoma of skin 4

Oral cavity and pharynx 3

Kidney and renal pelvis 3

Leukemia 2

Pancreas 2

All other sites 19

FemaleProstate 30

Lung and bronchus 12

Colon and rectum 11

Urinary bladder 6

Non-Hodgkinrsquos Lymphoma 4

Melanoma of skin 4

Oral cavity and pharynx 3

Kidney and renal pelvis 2

Leukemia 2

Pancreas 2

All other sites 22

Average Annual Age-Specific US Average Annual Age-Specific US Incidence and Mortality Rates of CRC Incidence and Mortality Rates of CRC

1992-19961992-1996

Prevalence of Adenomas and Prevalence of Adenomas and Incidence of Colon CancerIncidence of Colon Cancer

Age gt50 years with any adenomas 25-40

Lifetime risk of cancer at age 50 years 5 for females 6 for males

Persons with advanced adenomas are at greatest risk

Risk Factors for Colorectal Cancer Risk Factors for Colorectal Cancer (CRC)(CRC)

Aging Personal history of CRC or adenomas High-fat low-fiber diet Inflammatory bowel disease Family history of CRC Hereditary colon cancer syndromes

Risk of Colorectal Cancer Risk of Colorectal Cancer (CRC)(CRC)

0 20 40 60 80 100

Personal History of Colorectal Neoplasia

General Population

Inflammatory Bowel Disease

Familial Adenomatous Polyposis

(FAP)

HNPCC Mutation

Lifetime Risk ()

5

15-20

15-40

70-80

gt95

Colorectal CancerColorectal CancerStatistics in the USStatistics in the US

Second overall leading cause of cancer-related deaths in the US

Estimated 149000 new cases and 50000 deaths in the year 2008

Declining trends between 1990 and 1996 Incidence rate ~21 per year Mortality rates ~17 per year

Family History Empiric RisksFamily History Empiric RisksLifetime Risk CRC

General population in US ~2 to 6

One 1st degree relative with CRC 2-3 fold

Two 1st degree relatives with CRC 3-4 fold

1st degree relative with CRC lt50 3-4 fold

One 2nd or 3rd degree relative with CRC

~15 fold

Two 2nd degree relatives with CRC 2-3 fold

OutlineOutline Hereditary colorectal cancer syndromes Cancer family history ndash a primary tool Evaluating your patients for familial CRC risk Genetic counseling and testing for hereditary

colorectal cancer How when where to refer patients for genetic

services

Colorectal CancerColorectal Cancer

~5-8 of all cases of CRC are hereditary

~15-20 are ldquofamilialrdquomultifactorial

~75 of cases are sporadic

Characteristics of Average RiskCharacteristics of Average Risk

No well-defined threshold between sporadic and familial CRC at this time

Probably safe to include individuals with No personal risk factors or family history of CRC One 2nd or 3rd degree relative with CRC gt60 years with no

other family history of CRC

Characteristics of ldquoFamilialrdquo CRCCharacteristics of ldquoFamilialrdquo CRC

ldquoClusteringrdquo of colon cancer cases in the family (gt50 at diagnosis) without clear dominant pattern or

One close relative with CRC lt60 years and family history does not meet criteria for known hereditary CRC syndromes

Likely to be multiple low penetrant genes plus environmental factors at play

Family members warrant earlier CRC screening Starting at 40 years or 5-10 years earlier than age of diagnosis

of the youngest affected relative

Characteristics of Hereditary Characteristics of Hereditary CRCCRC

Multiple relatives with colorectal cancer One or more diagnosed at an early age (lt50)

Sequential generations affected Except in autosomal recessive syndromes

Other cancers in the family known to be associated with CRC (uterine ovarian GI)

Multiple primary tumors or polyps

Hereditary CRC SyndromesHereditary CRC Syndromes Hereditary Non-Polyposis Colorectal Cancer (HNPCC)

Variants Muir-Torre Turcot Familial Adenomatous Polyposis (FAP)

Variants Gardner Turcot Attenuated FAP APC mutation in Ashkenazi Jews

Others Multiple adenomatous polyposis syndromeMYH gene (MAP) Peutz-Jeghers syndrome (PJS) Familial Juvenile Polyposis (FJP)

HNPCC AKA ldquoLynch SyndromerdquoHNPCC AKA ldquoLynch Syndromerdquo

2-3 of all colorectal cancer cases Autosomal dominant high penetrance Typical age of CA onset is 40-50 years Multiple affected generations 60-70 right-sidedproximal CRC tumors Polyps may be present multiple primaries

common Can overlap with AFAP

HNPCCHNPCCbull Lifetime cancer risks

ndash Colorectal 80

ndash Endometrial 20-60

ndash Gastric 13-19

ndash Ovarian 9-12

ndash Biliary Tract 2

ndash Urinary Tract 4

ndash Small Bowel 1-4

ndash BrainCNS 1-3

HNPCCHNPCCClinical Diagnostic CriteriaClinical Diagnostic Criteria

Amsterdam II Criteria (3-2-1) 3 or more relatives with an HNPCC-related cancer

one of whom is a 1st degree relative of the other two 2 or more successive generations affected

1 or more cancers diagnosed before age 50

HNPCCHNPCC Caused by mutations or deletions in mismatched

repair (MMR) genes MSH2 MLH1 MSH6 (PMS2)

50 of families meeting Amsterdam II Criteria have detectable mutations

TestingScreening options Direct genetic testing of MMR genes (in select families) Initial screening of the tumor tissue by MSIIHC

MSIIHC ScreeningMSIIHC Screening Microsatellite Instability (MSI) on tumor tissue

can be used to screen for HNPCC in select cases

Immunohistochemistry (IHC) on tumor tissue

can be used to detect the presence or absence of the mismatch repair proteins (MSH2 MLH1 etc)

ldquoScreen positiverdquo individuals can be offered cancer genetic counselingassessment and targeted genetic testing

FAPFAP 1 in 10000 incidence 100rsquos to 1000rsquos of colonic adenomas by teens

Cancer risk colon gastric duodenum (periampulla) small bowel pancreas papillary thyroid childhood hepatoblastoma

7 risk of CRC by 21 yrs 93 by 50 yrs Autosomal dominant APC gene mutations Variants Gardner Turcot

FAP - SurveillanceFAP - Surveillance Colon

Annual sigmoidoscopy age 10-12 yrs Prophylactic colectomy following polyp detection with

continued surveillance of rectum ileal pouch Duodenalgastric

EGD age 25 repeat 1-3 yrs Thyroid

Annual PE age 10 Hepatoblastoma

Annual screen by abd US amp AFP from birth to 5 yrs

Attenuated FAPAttenuated FAP 20 to 100 polyps usually more proximal

Onset later than FAP average AOO = 50 Lifetime risk of CRC = 80

Extracolonic tumors occur at same rate as FAP Variant of FAP mutations in same APC gene Surveillance

annual colonoscopy starting late teens or early 20rsquos Option of subtotal colectomy

Genetic Testing FAPAFAPGenetic Testing FAPAFAP Test an affected family member first

After genetic counseling and informed consent

APC gene testing can confirm a suspected diagnosis

Family members of a person with a known APC mutation can have mutation-specific testing

Genetic testing for children at risk for FAP can be considered before beginning colon screening

APC gene mutation inAPC gene mutation inAshkenazi JewsAshkenazi Jews

Missense mutation (I1307K) associated with increased risk of CRC and adenomas in Ashkenazi Jews (AJ)

Found in 6 of the general AJ population

12 of AJs with CRC

29 of AJs with CRC and a positive family history

Lifetime risk of CRC in mutation carrier is 10-20

Screening colonoscopy every 2-5 yrs starting at 35 yrs

MAP syndromeMYH geneMAP syndromeMYH gene Multiple adenomatous polyposis (MAP) syndrome

Autosomal recessive mutations in the MYH gene Median number of polyps = 55 Mean age of polyp diagnosis = 30-50 years Polyps mainly small mildly dysplastic tubular adenomas Some

tubulovillous hyperplastic serrated adenomas microadenomas

30 of individuals with 15-100 polyps have homozygous mutations in the MYH gene

Genetic testing should be offered if gt15 polyps (and APC gene testing negative)

Peutz-Jeghers SyndromePeutz-Jeghers Syndrome lt1 of all CRC cases Hamartomatous polyps of GI tract as early as 1st decade Mucocutaneous hyper pigmentation

lips mouth buccal mucosa fingers Usually seen in children lt 5 yrs

Cancer risk colon small intestine stomach pancreas breast ovaries uterus testes

lungs kidneys Mutations in STK11 gene

found in 70 of familial cases and 30-70 of sporadic cases

Familial Juvenile PolyposisFamilial Juvenile Polyposis

lt1 of all CRC cases

Autosomal dominant

5 or more juvenile polyps in colon or GI tract

Appear in 1st or 2nd decade

50 lifetime risk of CRC AOO in 30rsquos

Increased risk gastric GI pancreatic CA

~50 of cases have mutations in either the MADH4 or BMPR1A genes

Family Health HistoryFamily Health History

ldquoThe family tree has become the most important genetic test of all The more you know the more tools you have to practice preventive medicinerdquo

Donna Russo Certified Genetic Counselor NY Presbyterian-Columbia Hospital

Goal ClassificationGoal ClassificationAssessment Risk Classification Intervention

Family History

Average

Moderate

(ldquoFamilialrdquo)

HighGenetic

Personalized prevention recommendations

Standard prevention recommendations

Referral for genetic evaluation with personalized prevention recommendations

Consider Genetics Referral forConsider Genetics Referral for

Two or more family members with CRC at least one lt50

Three or more family members wCRC any age

Patient with colon cancer before 40 yrs

Endometrial cancer and family history of CRC lt50

Persons with more than one primary CRC lt50 yrs or with both endometrial CA and CRC

Family or personal history of CRC and one or more 1st degree relative with an HNPCC-related cancer one diagnosed lt50 yrs

Same side of family

Consider Genetics Referral forConsider Genetics Referral for

MSI andor IHC tumor results suspicious for HNPCC

Autosomal dominant pattern of cancers in the family

Persons with 15 or more adenomatous colorectal polyps

Persons with multiple hamartomatous or juvenile GI polyps

Persons with a family history of a known hereditary cancer syndrome

CRC Risk ManagementCRC Risk Management

Average Risk

1 No family history CRC OR2 One 2nd or 3rd degree relative with CRC

FOBT annually + flex sig every 5 years OR Colonoscopy every 10 years OR DCBE every 5 years

Age to Begin50 years

CRC Risk ManagementCRC Risk ManagementModerateFamily history Two 1st degree relatives with CRC any age

or one 1st degree relative with CRC lt 60- Colonoscopy every 5 yrs

One 1st degree relative with CRC gt60 or two 2nd degree relatives with CRC any age- Average risk screening

Or 5-10 yrs earlier than earliest case in family

Age to begin

40 years

40 years

CRC Risk ManagementCRC Risk Management

Age to Begin

HNPCC or suspected HNPCC 20-25 years 1 Colonoscopy every 1-2 yrs

2 Genetic counseling consider genetic testing

FAP or suspected FAP 10-12 years 1 Flex sig or colonoscopy every1-2 yrs

2 Genetic counseling consider genetic testing

Case 1 JoanCase 1 Joan Joan age 38 was recently diagnosed with

endometrial cancer Family history reveals

1 Paternal grandmother endometrial cancer age 50 2 Paternal uncle colon cancer age 48 3 Father colonoscopy at age 50 four adenomatous

polyps removed 4 No other significant history 5 Both sides of the family are Northern European

Caucasian

Pedigree Case 1Pedigree Case 1French Irish Scottish German English

88 yr

61 yr 63 yr

4 polyps

50 yrs 38 yr

35 yrDx 38

8 yr10 yr

CRC Dx 48

Dx 50

KEYKEY

Endometrial CA

Colorectal CA

Adenomatous Polyps

Case 1 AssessmentCase 1 Assessment Joan meets Amsterdam II Criteria and is at risk for HNPCC

Refer to genetics for cancer genetic counseling and discussion of genetic testing for HNPCC

Testing options

1 Direct gene testing of MLH1 and MSH2 OR

2 MSIIHC screening of tumor tissue with gene sequencing if MSI positive

Case 2 TedCase 2 Ted Ted is 30 and wants a colonoscopy because his mother

was just diagnosed with colon cancer after routine screening at age 54 Family history reveals

1 Paternal grandfather died of CRC at age 79

2 No hx of endometrial ovarian small bowel or ureterkidney cancer on either side of family

3 Two maternal aunts cervical cancer at ages 30 amp 34

4 Maternal grandmother breast cancer age 85

Pedigree Case 2Pedigree Case 2Italian Irish German

KEY

CRC

Breast CA

Cervical CA

84

d 58 MIBrCa 85 yrs

d87

55 58 60

Colon CA 54 yrs

Cervical CA 30 yrs

Cervical CA 32 yrs

34 yrs 30 yrs

CRC 79 d82

56

Case 2 TedCase 2 Ted Verify Diagnoses Obtain and review pathology reports on

all reported cancers whenever possible

If diagnoses are correct Ted has no family history indicative of a known colon cancer syndrome (HNPCC FAP other)

Tedrsquos lifetime risk of colorectal CA is increased 2 to 3 fold due to one affected first degree relative (gt50)

Moderatefamilial risk Screening by colonoscopy starting at age 40 or 10 yrs earlier than earliest case in family is reasonable

Chemo PreventionChemo Prevention Evidence that ASA NSAIDs Calcium and COX-2

inhibitors may reduce incidence of CA by reducing ofadenomas

1048707 40-50 risk reduction for developing colorectal CA regardless of location in colon age gender and race

Generally performed by RCTrsquos in patients with priorcolorectal CA followed for recurrence of adenomas

Diet fiber and antioxidant vitamins have not beenshown by RCTrsquos to decrease risk of recurrent adenomas

COX-2irsquos and Sulindac have been shown to reduce thenumber of adenomas found in FAP alone

1048707 Not effective for sporadic colon CA 1048707 Actually can cause regression of adenomas

Cancer is a Disease of the Cell CycleCancer is a Disease of the Cell Cycle

ldquoCarcinoma is a genetic disease it is not necessarily inheritedrdquo

Knudsenrsquos ldquotwo hitrdquo hypothesisKnudsenrsquos ldquotwo hitrdquo hypothesis

Types of genes which may mutate Types of genes which may mutate to cause cancerto cause cancer

Oncogenes Suppressor genes DNA repair genes p53

Adenoma-Carcinoma SequenceAdenoma-Carcinoma SequenceAccumulation of MutationsAccumulation of Mutations

DCC MCC p53 K-ras APC MSH2 MLH1 etcDCC MCC p53 K-ras APC MSH2 MLH1 etc

Estimated New Cancer Cases of 10 Estimated New Cancer Cases of 10 Leading Sites by Gender for the US 2000Leading Sites by Gender for the US 2000

MaleProstate 29

Lung and bronchus 14

Colon and rectum 10

Urinary bladder 6

Non-Hodgkinrsquos Lymphoma 5

Melanoma of skin 4

Oral cavity and pharynx 3

Kidney and renal pelvis 3

Leukemia 2

Pancreas 2

All other sites 19

FemaleProstate 30

Lung and bronchus 12

Colon and rectum 11

Urinary bladder 6

Non-Hodgkinrsquos Lymphoma 4

Melanoma of skin 4

Oral cavity and pharynx 3

Kidney and renal pelvis 2

Leukemia 2

Pancreas 2

All other sites 22

Average Annual Age-Specific US Average Annual Age-Specific US Incidence and Mortality Rates of CRC Incidence and Mortality Rates of CRC

1992-19961992-1996

Prevalence of Adenomas and Prevalence of Adenomas and Incidence of Colon CancerIncidence of Colon Cancer

Age gt50 years with any adenomas 25-40

Lifetime risk of cancer at age 50 years 5 for females 6 for males

Persons with advanced adenomas are at greatest risk

Risk Factors for Colorectal Cancer Risk Factors for Colorectal Cancer (CRC)(CRC)

Aging Personal history of CRC or adenomas High-fat low-fiber diet Inflammatory bowel disease Family history of CRC Hereditary colon cancer syndromes

Risk of Colorectal Cancer Risk of Colorectal Cancer (CRC)(CRC)

0 20 40 60 80 100

Personal History of Colorectal Neoplasia

General Population

Inflammatory Bowel Disease

Familial Adenomatous Polyposis

(FAP)

HNPCC Mutation

Lifetime Risk ()

5

15-20

15-40

70-80

gt95

Colorectal CancerColorectal CancerStatistics in the USStatistics in the US

Second overall leading cause of cancer-related deaths in the US

Estimated 149000 new cases and 50000 deaths in the year 2008

Declining trends between 1990 and 1996 Incidence rate ~21 per year Mortality rates ~17 per year

Family History Empiric RisksFamily History Empiric RisksLifetime Risk CRC

General population in US ~2 to 6

One 1st degree relative with CRC 2-3 fold

Two 1st degree relatives with CRC 3-4 fold

1st degree relative with CRC lt50 3-4 fold

One 2nd or 3rd degree relative with CRC

~15 fold

Two 2nd degree relatives with CRC 2-3 fold

OutlineOutline Hereditary colorectal cancer syndromes Cancer family history ndash a primary tool Evaluating your patients for familial CRC risk Genetic counseling and testing for hereditary

colorectal cancer How when where to refer patients for genetic

services

Colorectal CancerColorectal Cancer

~5-8 of all cases of CRC are hereditary

~15-20 are ldquofamilialrdquomultifactorial

~75 of cases are sporadic

Characteristics of Average RiskCharacteristics of Average Risk

No well-defined threshold between sporadic and familial CRC at this time

Probably safe to include individuals with No personal risk factors or family history of CRC One 2nd or 3rd degree relative with CRC gt60 years with no

other family history of CRC

Characteristics of ldquoFamilialrdquo CRCCharacteristics of ldquoFamilialrdquo CRC

ldquoClusteringrdquo of colon cancer cases in the family (gt50 at diagnosis) without clear dominant pattern or

One close relative with CRC lt60 years and family history does not meet criteria for known hereditary CRC syndromes

Likely to be multiple low penetrant genes plus environmental factors at play

Family members warrant earlier CRC screening Starting at 40 years or 5-10 years earlier than age of diagnosis

of the youngest affected relative

Characteristics of Hereditary Characteristics of Hereditary CRCCRC

Multiple relatives with colorectal cancer One or more diagnosed at an early age (lt50)

Sequential generations affected Except in autosomal recessive syndromes

Other cancers in the family known to be associated with CRC (uterine ovarian GI)

Multiple primary tumors or polyps

Hereditary CRC SyndromesHereditary CRC Syndromes Hereditary Non-Polyposis Colorectal Cancer (HNPCC)

Variants Muir-Torre Turcot Familial Adenomatous Polyposis (FAP)

Variants Gardner Turcot Attenuated FAP APC mutation in Ashkenazi Jews

Others Multiple adenomatous polyposis syndromeMYH gene (MAP) Peutz-Jeghers syndrome (PJS) Familial Juvenile Polyposis (FJP)

HNPCC AKA ldquoLynch SyndromerdquoHNPCC AKA ldquoLynch Syndromerdquo

2-3 of all colorectal cancer cases Autosomal dominant high penetrance Typical age of CA onset is 40-50 years Multiple affected generations 60-70 right-sidedproximal CRC tumors Polyps may be present multiple primaries

common Can overlap with AFAP

HNPCCHNPCCbull Lifetime cancer risks

ndash Colorectal 80

ndash Endometrial 20-60

ndash Gastric 13-19

ndash Ovarian 9-12

ndash Biliary Tract 2

ndash Urinary Tract 4

ndash Small Bowel 1-4

ndash BrainCNS 1-3

HNPCCHNPCCClinical Diagnostic CriteriaClinical Diagnostic Criteria

Amsterdam II Criteria (3-2-1) 3 or more relatives with an HNPCC-related cancer

one of whom is a 1st degree relative of the other two 2 or more successive generations affected

1 or more cancers diagnosed before age 50

HNPCCHNPCC Caused by mutations or deletions in mismatched

repair (MMR) genes MSH2 MLH1 MSH6 (PMS2)

50 of families meeting Amsterdam II Criteria have detectable mutations

TestingScreening options Direct genetic testing of MMR genes (in select families) Initial screening of the tumor tissue by MSIIHC

MSIIHC ScreeningMSIIHC Screening Microsatellite Instability (MSI) on tumor tissue

can be used to screen for HNPCC in select cases

Immunohistochemistry (IHC) on tumor tissue

can be used to detect the presence or absence of the mismatch repair proteins (MSH2 MLH1 etc)

ldquoScreen positiverdquo individuals can be offered cancer genetic counselingassessment and targeted genetic testing

FAPFAP 1 in 10000 incidence 100rsquos to 1000rsquos of colonic adenomas by teens

Cancer risk colon gastric duodenum (periampulla) small bowel pancreas papillary thyroid childhood hepatoblastoma

7 risk of CRC by 21 yrs 93 by 50 yrs Autosomal dominant APC gene mutations Variants Gardner Turcot

FAP - SurveillanceFAP - Surveillance Colon

Annual sigmoidoscopy age 10-12 yrs Prophylactic colectomy following polyp detection with

continued surveillance of rectum ileal pouch Duodenalgastric

EGD age 25 repeat 1-3 yrs Thyroid

Annual PE age 10 Hepatoblastoma

Annual screen by abd US amp AFP from birth to 5 yrs

Attenuated FAPAttenuated FAP 20 to 100 polyps usually more proximal

Onset later than FAP average AOO = 50 Lifetime risk of CRC = 80

Extracolonic tumors occur at same rate as FAP Variant of FAP mutations in same APC gene Surveillance

annual colonoscopy starting late teens or early 20rsquos Option of subtotal colectomy

Genetic Testing FAPAFAPGenetic Testing FAPAFAP Test an affected family member first

After genetic counseling and informed consent

APC gene testing can confirm a suspected diagnosis

Family members of a person with a known APC mutation can have mutation-specific testing

Genetic testing for children at risk for FAP can be considered before beginning colon screening

APC gene mutation inAPC gene mutation inAshkenazi JewsAshkenazi Jews

Missense mutation (I1307K) associated with increased risk of CRC and adenomas in Ashkenazi Jews (AJ)

Found in 6 of the general AJ population

12 of AJs with CRC

29 of AJs with CRC and a positive family history

Lifetime risk of CRC in mutation carrier is 10-20

Screening colonoscopy every 2-5 yrs starting at 35 yrs

MAP syndromeMYH geneMAP syndromeMYH gene Multiple adenomatous polyposis (MAP) syndrome

Autosomal recessive mutations in the MYH gene Median number of polyps = 55 Mean age of polyp diagnosis = 30-50 years Polyps mainly small mildly dysplastic tubular adenomas Some

tubulovillous hyperplastic serrated adenomas microadenomas

30 of individuals with 15-100 polyps have homozygous mutations in the MYH gene

Genetic testing should be offered if gt15 polyps (and APC gene testing negative)

Peutz-Jeghers SyndromePeutz-Jeghers Syndrome lt1 of all CRC cases Hamartomatous polyps of GI tract as early as 1st decade Mucocutaneous hyper pigmentation

lips mouth buccal mucosa fingers Usually seen in children lt 5 yrs

Cancer risk colon small intestine stomach pancreas breast ovaries uterus testes

lungs kidneys Mutations in STK11 gene

found in 70 of familial cases and 30-70 of sporadic cases

Familial Juvenile PolyposisFamilial Juvenile Polyposis

lt1 of all CRC cases

Autosomal dominant

5 or more juvenile polyps in colon or GI tract

Appear in 1st or 2nd decade

50 lifetime risk of CRC AOO in 30rsquos

Increased risk gastric GI pancreatic CA

~50 of cases have mutations in either the MADH4 or BMPR1A genes

Family Health HistoryFamily Health History

ldquoThe family tree has become the most important genetic test of all The more you know the more tools you have to practice preventive medicinerdquo

Donna Russo Certified Genetic Counselor NY Presbyterian-Columbia Hospital

Goal ClassificationGoal ClassificationAssessment Risk Classification Intervention

Family History

Average

Moderate

(ldquoFamilialrdquo)

HighGenetic

Personalized prevention recommendations

Standard prevention recommendations

Referral for genetic evaluation with personalized prevention recommendations

Consider Genetics Referral forConsider Genetics Referral for

Two or more family members with CRC at least one lt50

Three or more family members wCRC any age

Patient with colon cancer before 40 yrs

Endometrial cancer and family history of CRC lt50

Persons with more than one primary CRC lt50 yrs or with both endometrial CA and CRC

Family or personal history of CRC and one or more 1st degree relative with an HNPCC-related cancer one diagnosed lt50 yrs

Same side of family

Consider Genetics Referral forConsider Genetics Referral for

MSI andor IHC tumor results suspicious for HNPCC

Autosomal dominant pattern of cancers in the family

Persons with 15 or more adenomatous colorectal polyps

Persons with multiple hamartomatous or juvenile GI polyps

Persons with a family history of a known hereditary cancer syndrome

CRC Risk ManagementCRC Risk Management

Average Risk

1 No family history CRC OR2 One 2nd or 3rd degree relative with CRC

FOBT annually + flex sig every 5 years OR Colonoscopy every 10 years OR DCBE every 5 years

Age to Begin50 years

CRC Risk ManagementCRC Risk ManagementModerateFamily history Two 1st degree relatives with CRC any age

or one 1st degree relative with CRC lt 60- Colonoscopy every 5 yrs

One 1st degree relative with CRC gt60 or two 2nd degree relatives with CRC any age- Average risk screening

Or 5-10 yrs earlier than earliest case in family

Age to begin

40 years

40 years

CRC Risk ManagementCRC Risk Management

Age to Begin

HNPCC or suspected HNPCC 20-25 years 1 Colonoscopy every 1-2 yrs

2 Genetic counseling consider genetic testing

FAP or suspected FAP 10-12 years 1 Flex sig or colonoscopy every1-2 yrs

2 Genetic counseling consider genetic testing

Case 1 JoanCase 1 Joan Joan age 38 was recently diagnosed with

endometrial cancer Family history reveals

1 Paternal grandmother endometrial cancer age 50 2 Paternal uncle colon cancer age 48 3 Father colonoscopy at age 50 four adenomatous

polyps removed 4 No other significant history 5 Both sides of the family are Northern European

Caucasian

Pedigree Case 1Pedigree Case 1French Irish Scottish German English

88 yr

61 yr 63 yr

4 polyps

50 yrs 38 yr

35 yrDx 38

8 yr10 yr

CRC Dx 48

Dx 50

KEYKEY

Endometrial CA

Colorectal CA

Adenomatous Polyps

Case 1 AssessmentCase 1 Assessment Joan meets Amsterdam II Criteria and is at risk for HNPCC

Refer to genetics for cancer genetic counseling and discussion of genetic testing for HNPCC

Testing options

1 Direct gene testing of MLH1 and MSH2 OR

2 MSIIHC screening of tumor tissue with gene sequencing if MSI positive

Case 2 TedCase 2 Ted Ted is 30 and wants a colonoscopy because his mother

was just diagnosed with colon cancer after routine screening at age 54 Family history reveals

1 Paternal grandfather died of CRC at age 79

2 No hx of endometrial ovarian small bowel or ureterkidney cancer on either side of family

3 Two maternal aunts cervical cancer at ages 30 amp 34

4 Maternal grandmother breast cancer age 85

Pedigree Case 2Pedigree Case 2Italian Irish German

KEY

CRC

Breast CA

Cervical CA

84

d 58 MIBrCa 85 yrs

d87

55 58 60

Colon CA 54 yrs

Cervical CA 30 yrs

Cervical CA 32 yrs

34 yrs 30 yrs

CRC 79 d82

56

Case 2 TedCase 2 Ted Verify Diagnoses Obtain and review pathology reports on

all reported cancers whenever possible

If diagnoses are correct Ted has no family history indicative of a known colon cancer syndrome (HNPCC FAP other)

Tedrsquos lifetime risk of colorectal CA is increased 2 to 3 fold due to one affected first degree relative (gt50)

Moderatefamilial risk Screening by colonoscopy starting at age 40 or 10 yrs earlier than earliest case in family is reasonable

Chemo PreventionChemo Prevention Evidence that ASA NSAIDs Calcium and COX-2

inhibitors may reduce incidence of CA by reducing ofadenomas

1048707 40-50 risk reduction for developing colorectal CA regardless of location in colon age gender and race

Generally performed by RCTrsquos in patients with priorcolorectal CA followed for recurrence of adenomas

Diet fiber and antioxidant vitamins have not beenshown by RCTrsquos to decrease risk of recurrent adenomas

COX-2irsquos and Sulindac have been shown to reduce thenumber of adenomas found in FAP alone

1048707 Not effective for sporadic colon CA 1048707 Actually can cause regression of adenomas

Knudsenrsquos ldquotwo hitrdquo hypothesisKnudsenrsquos ldquotwo hitrdquo hypothesis

Types of genes which may mutate Types of genes which may mutate to cause cancerto cause cancer

Oncogenes Suppressor genes DNA repair genes p53

Adenoma-Carcinoma SequenceAdenoma-Carcinoma SequenceAccumulation of MutationsAccumulation of Mutations

DCC MCC p53 K-ras APC MSH2 MLH1 etcDCC MCC p53 K-ras APC MSH2 MLH1 etc

Estimated New Cancer Cases of 10 Estimated New Cancer Cases of 10 Leading Sites by Gender for the US 2000Leading Sites by Gender for the US 2000

MaleProstate 29

Lung and bronchus 14

Colon and rectum 10

Urinary bladder 6

Non-Hodgkinrsquos Lymphoma 5

Melanoma of skin 4

Oral cavity and pharynx 3

Kidney and renal pelvis 3

Leukemia 2

Pancreas 2

All other sites 19

FemaleProstate 30

Lung and bronchus 12

Colon and rectum 11

Urinary bladder 6

Non-Hodgkinrsquos Lymphoma 4

Melanoma of skin 4

Oral cavity and pharynx 3

Kidney and renal pelvis 2

Leukemia 2

Pancreas 2

All other sites 22

Average Annual Age-Specific US Average Annual Age-Specific US Incidence and Mortality Rates of CRC Incidence and Mortality Rates of CRC

1992-19961992-1996

Prevalence of Adenomas and Prevalence of Adenomas and Incidence of Colon CancerIncidence of Colon Cancer

Age gt50 years with any adenomas 25-40

Lifetime risk of cancer at age 50 years 5 for females 6 for males

Persons with advanced adenomas are at greatest risk

Risk Factors for Colorectal Cancer Risk Factors for Colorectal Cancer (CRC)(CRC)

Aging Personal history of CRC or adenomas High-fat low-fiber diet Inflammatory bowel disease Family history of CRC Hereditary colon cancer syndromes

Risk of Colorectal Cancer Risk of Colorectal Cancer (CRC)(CRC)

0 20 40 60 80 100

Personal History of Colorectal Neoplasia

General Population

Inflammatory Bowel Disease

Familial Adenomatous Polyposis

(FAP)

HNPCC Mutation

Lifetime Risk ()

5

15-20

15-40

70-80

gt95

Colorectal CancerColorectal CancerStatistics in the USStatistics in the US

Second overall leading cause of cancer-related deaths in the US

Estimated 149000 new cases and 50000 deaths in the year 2008

Declining trends between 1990 and 1996 Incidence rate ~21 per year Mortality rates ~17 per year

Family History Empiric RisksFamily History Empiric RisksLifetime Risk CRC

General population in US ~2 to 6

One 1st degree relative with CRC 2-3 fold

Two 1st degree relatives with CRC 3-4 fold

1st degree relative with CRC lt50 3-4 fold

One 2nd or 3rd degree relative with CRC

~15 fold

Two 2nd degree relatives with CRC 2-3 fold

OutlineOutline Hereditary colorectal cancer syndromes Cancer family history ndash a primary tool Evaluating your patients for familial CRC risk Genetic counseling and testing for hereditary

colorectal cancer How when where to refer patients for genetic

services

Colorectal CancerColorectal Cancer

~5-8 of all cases of CRC are hereditary

~15-20 are ldquofamilialrdquomultifactorial

~75 of cases are sporadic

Characteristics of Average RiskCharacteristics of Average Risk

No well-defined threshold between sporadic and familial CRC at this time

Probably safe to include individuals with No personal risk factors or family history of CRC One 2nd or 3rd degree relative with CRC gt60 years with no

other family history of CRC

Characteristics of ldquoFamilialrdquo CRCCharacteristics of ldquoFamilialrdquo CRC

ldquoClusteringrdquo of colon cancer cases in the family (gt50 at diagnosis) without clear dominant pattern or

One close relative with CRC lt60 years and family history does not meet criteria for known hereditary CRC syndromes

Likely to be multiple low penetrant genes plus environmental factors at play

Family members warrant earlier CRC screening Starting at 40 years or 5-10 years earlier than age of diagnosis

of the youngest affected relative

Characteristics of Hereditary Characteristics of Hereditary CRCCRC

Multiple relatives with colorectal cancer One or more diagnosed at an early age (lt50)

Sequential generations affected Except in autosomal recessive syndromes

Other cancers in the family known to be associated with CRC (uterine ovarian GI)

Multiple primary tumors or polyps

Hereditary CRC SyndromesHereditary CRC Syndromes Hereditary Non-Polyposis Colorectal Cancer (HNPCC)

Variants Muir-Torre Turcot Familial Adenomatous Polyposis (FAP)

Variants Gardner Turcot Attenuated FAP APC mutation in Ashkenazi Jews

Others Multiple adenomatous polyposis syndromeMYH gene (MAP) Peutz-Jeghers syndrome (PJS) Familial Juvenile Polyposis (FJP)

HNPCC AKA ldquoLynch SyndromerdquoHNPCC AKA ldquoLynch Syndromerdquo

2-3 of all colorectal cancer cases Autosomal dominant high penetrance Typical age of CA onset is 40-50 years Multiple affected generations 60-70 right-sidedproximal CRC tumors Polyps may be present multiple primaries

common Can overlap with AFAP

HNPCCHNPCCbull Lifetime cancer risks

ndash Colorectal 80

ndash Endometrial 20-60

ndash Gastric 13-19

ndash Ovarian 9-12

ndash Biliary Tract 2

ndash Urinary Tract 4

ndash Small Bowel 1-4

ndash BrainCNS 1-3

HNPCCHNPCCClinical Diagnostic CriteriaClinical Diagnostic Criteria

Amsterdam II Criteria (3-2-1) 3 or more relatives with an HNPCC-related cancer

one of whom is a 1st degree relative of the other two 2 or more successive generations affected

1 or more cancers diagnosed before age 50

HNPCCHNPCC Caused by mutations or deletions in mismatched

repair (MMR) genes MSH2 MLH1 MSH6 (PMS2)

50 of families meeting Amsterdam II Criteria have detectable mutations

TestingScreening options Direct genetic testing of MMR genes (in select families) Initial screening of the tumor tissue by MSIIHC

MSIIHC ScreeningMSIIHC Screening Microsatellite Instability (MSI) on tumor tissue

can be used to screen for HNPCC in select cases

Immunohistochemistry (IHC) on tumor tissue

can be used to detect the presence or absence of the mismatch repair proteins (MSH2 MLH1 etc)

ldquoScreen positiverdquo individuals can be offered cancer genetic counselingassessment and targeted genetic testing

FAPFAP 1 in 10000 incidence 100rsquos to 1000rsquos of colonic adenomas by teens

Cancer risk colon gastric duodenum (periampulla) small bowel pancreas papillary thyroid childhood hepatoblastoma

7 risk of CRC by 21 yrs 93 by 50 yrs Autosomal dominant APC gene mutations Variants Gardner Turcot

FAP - SurveillanceFAP - Surveillance Colon

Annual sigmoidoscopy age 10-12 yrs Prophylactic colectomy following polyp detection with

continued surveillance of rectum ileal pouch Duodenalgastric

EGD age 25 repeat 1-3 yrs Thyroid

Annual PE age 10 Hepatoblastoma

Annual screen by abd US amp AFP from birth to 5 yrs

Attenuated FAPAttenuated FAP 20 to 100 polyps usually more proximal

Onset later than FAP average AOO = 50 Lifetime risk of CRC = 80

Extracolonic tumors occur at same rate as FAP Variant of FAP mutations in same APC gene Surveillance

annual colonoscopy starting late teens or early 20rsquos Option of subtotal colectomy

Genetic Testing FAPAFAPGenetic Testing FAPAFAP Test an affected family member first

After genetic counseling and informed consent

APC gene testing can confirm a suspected diagnosis

Family members of a person with a known APC mutation can have mutation-specific testing

Genetic testing for children at risk for FAP can be considered before beginning colon screening

APC gene mutation inAPC gene mutation inAshkenazi JewsAshkenazi Jews

Missense mutation (I1307K) associated with increased risk of CRC and adenomas in Ashkenazi Jews (AJ)

Found in 6 of the general AJ population

12 of AJs with CRC

29 of AJs with CRC and a positive family history

Lifetime risk of CRC in mutation carrier is 10-20

Screening colonoscopy every 2-5 yrs starting at 35 yrs

MAP syndromeMYH geneMAP syndromeMYH gene Multiple adenomatous polyposis (MAP) syndrome

Autosomal recessive mutations in the MYH gene Median number of polyps = 55 Mean age of polyp diagnosis = 30-50 years Polyps mainly small mildly dysplastic tubular adenomas Some

tubulovillous hyperplastic serrated adenomas microadenomas

30 of individuals with 15-100 polyps have homozygous mutations in the MYH gene

Genetic testing should be offered if gt15 polyps (and APC gene testing negative)

Peutz-Jeghers SyndromePeutz-Jeghers Syndrome lt1 of all CRC cases Hamartomatous polyps of GI tract as early as 1st decade Mucocutaneous hyper pigmentation

lips mouth buccal mucosa fingers Usually seen in children lt 5 yrs

Cancer risk colon small intestine stomach pancreas breast ovaries uterus testes

lungs kidneys Mutations in STK11 gene

found in 70 of familial cases and 30-70 of sporadic cases

Familial Juvenile PolyposisFamilial Juvenile Polyposis

lt1 of all CRC cases

Autosomal dominant

5 or more juvenile polyps in colon or GI tract

Appear in 1st or 2nd decade

50 lifetime risk of CRC AOO in 30rsquos

Increased risk gastric GI pancreatic CA

~50 of cases have mutations in either the MADH4 or BMPR1A genes

Family Health HistoryFamily Health History

ldquoThe family tree has become the most important genetic test of all The more you know the more tools you have to practice preventive medicinerdquo

Donna Russo Certified Genetic Counselor NY Presbyterian-Columbia Hospital

Goal ClassificationGoal ClassificationAssessment Risk Classification Intervention

Family History

Average

Moderate

(ldquoFamilialrdquo)

HighGenetic

Personalized prevention recommendations

Standard prevention recommendations

Referral for genetic evaluation with personalized prevention recommendations

Consider Genetics Referral forConsider Genetics Referral for

Two or more family members with CRC at least one lt50

Three or more family members wCRC any age

Patient with colon cancer before 40 yrs

Endometrial cancer and family history of CRC lt50

Persons with more than one primary CRC lt50 yrs or with both endometrial CA and CRC

Family or personal history of CRC and one or more 1st degree relative with an HNPCC-related cancer one diagnosed lt50 yrs

Same side of family

Consider Genetics Referral forConsider Genetics Referral for

MSI andor IHC tumor results suspicious for HNPCC

Autosomal dominant pattern of cancers in the family

Persons with 15 or more adenomatous colorectal polyps

Persons with multiple hamartomatous or juvenile GI polyps

Persons with a family history of a known hereditary cancer syndrome

CRC Risk ManagementCRC Risk Management

Average Risk

1 No family history CRC OR2 One 2nd or 3rd degree relative with CRC

FOBT annually + flex sig every 5 years OR Colonoscopy every 10 years OR DCBE every 5 years

Age to Begin50 years

CRC Risk ManagementCRC Risk ManagementModerateFamily history Two 1st degree relatives with CRC any age

or one 1st degree relative with CRC lt 60- Colonoscopy every 5 yrs

One 1st degree relative with CRC gt60 or two 2nd degree relatives with CRC any age- Average risk screening

Or 5-10 yrs earlier than earliest case in family

Age to begin

40 years

40 years

CRC Risk ManagementCRC Risk Management

Age to Begin

HNPCC or suspected HNPCC 20-25 years 1 Colonoscopy every 1-2 yrs

2 Genetic counseling consider genetic testing

FAP or suspected FAP 10-12 years 1 Flex sig or colonoscopy every1-2 yrs

2 Genetic counseling consider genetic testing

Case 1 JoanCase 1 Joan Joan age 38 was recently diagnosed with

endometrial cancer Family history reveals

1 Paternal grandmother endometrial cancer age 50 2 Paternal uncle colon cancer age 48 3 Father colonoscopy at age 50 four adenomatous

polyps removed 4 No other significant history 5 Both sides of the family are Northern European

Caucasian

Pedigree Case 1Pedigree Case 1French Irish Scottish German English

88 yr

61 yr 63 yr

4 polyps

50 yrs 38 yr

35 yrDx 38

8 yr10 yr

CRC Dx 48

Dx 50

KEYKEY

Endometrial CA

Colorectal CA

Adenomatous Polyps

Case 1 AssessmentCase 1 Assessment Joan meets Amsterdam II Criteria and is at risk for HNPCC

Refer to genetics for cancer genetic counseling and discussion of genetic testing for HNPCC

Testing options

1 Direct gene testing of MLH1 and MSH2 OR

2 MSIIHC screening of tumor tissue with gene sequencing if MSI positive

Case 2 TedCase 2 Ted Ted is 30 and wants a colonoscopy because his mother

was just diagnosed with colon cancer after routine screening at age 54 Family history reveals

1 Paternal grandfather died of CRC at age 79

2 No hx of endometrial ovarian small bowel or ureterkidney cancer on either side of family

3 Two maternal aunts cervical cancer at ages 30 amp 34

4 Maternal grandmother breast cancer age 85

Pedigree Case 2Pedigree Case 2Italian Irish German

KEY

CRC

Breast CA

Cervical CA

84

d 58 MIBrCa 85 yrs

d87

55 58 60

Colon CA 54 yrs

Cervical CA 30 yrs

Cervical CA 32 yrs

34 yrs 30 yrs

CRC 79 d82

56

Case 2 TedCase 2 Ted Verify Diagnoses Obtain and review pathology reports on

all reported cancers whenever possible

If diagnoses are correct Ted has no family history indicative of a known colon cancer syndrome (HNPCC FAP other)

Tedrsquos lifetime risk of colorectal CA is increased 2 to 3 fold due to one affected first degree relative (gt50)

Moderatefamilial risk Screening by colonoscopy starting at age 40 or 10 yrs earlier than earliest case in family is reasonable

Chemo PreventionChemo Prevention Evidence that ASA NSAIDs Calcium and COX-2

inhibitors may reduce incidence of CA by reducing ofadenomas

1048707 40-50 risk reduction for developing colorectal CA regardless of location in colon age gender and race

Generally performed by RCTrsquos in patients with priorcolorectal CA followed for recurrence of adenomas

Diet fiber and antioxidant vitamins have not beenshown by RCTrsquos to decrease risk of recurrent adenomas

COX-2irsquos and Sulindac have been shown to reduce thenumber of adenomas found in FAP alone

1048707 Not effective for sporadic colon CA 1048707 Actually can cause regression of adenomas

Types of genes which may mutate Types of genes which may mutate to cause cancerto cause cancer

Oncogenes Suppressor genes DNA repair genes p53

Adenoma-Carcinoma SequenceAdenoma-Carcinoma SequenceAccumulation of MutationsAccumulation of Mutations

DCC MCC p53 K-ras APC MSH2 MLH1 etcDCC MCC p53 K-ras APC MSH2 MLH1 etc

Estimated New Cancer Cases of 10 Estimated New Cancer Cases of 10 Leading Sites by Gender for the US 2000Leading Sites by Gender for the US 2000

MaleProstate 29

Lung and bronchus 14

Colon and rectum 10

Urinary bladder 6

Non-Hodgkinrsquos Lymphoma 5

Melanoma of skin 4

Oral cavity and pharynx 3

Kidney and renal pelvis 3

Leukemia 2

Pancreas 2

All other sites 19

FemaleProstate 30

Lung and bronchus 12

Colon and rectum 11

Urinary bladder 6

Non-Hodgkinrsquos Lymphoma 4

Melanoma of skin 4

Oral cavity and pharynx 3

Kidney and renal pelvis 2

Leukemia 2

Pancreas 2

All other sites 22

Average Annual Age-Specific US Average Annual Age-Specific US Incidence and Mortality Rates of CRC Incidence and Mortality Rates of CRC

1992-19961992-1996

Prevalence of Adenomas and Prevalence of Adenomas and Incidence of Colon CancerIncidence of Colon Cancer

Age gt50 years with any adenomas 25-40

Lifetime risk of cancer at age 50 years 5 for females 6 for males

Persons with advanced adenomas are at greatest risk

Risk Factors for Colorectal Cancer Risk Factors for Colorectal Cancer (CRC)(CRC)

Aging Personal history of CRC or adenomas High-fat low-fiber diet Inflammatory bowel disease Family history of CRC Hereditary colon cancer syndromes

Risk of Colorectal Cancer Risk of Colorectal Cancer (CRC)(CRC)

0 20 40 60 80 100

Personal History of Colorectal Neoplasia

General Population

Inflammatory Bowel Disease

Familial Adenomatous Polyposis

(FAP)

HNPCC Mutation

Lifetime Risk ()

5

15-20

15-40

70-80

gt95

Colorectal CancerColorectal CancerStatistics in the USStatistics in the US

Second overall leading cause of cancer-related deaths in the US

Estimated 149000 new cases and 50000 deaths in the year 2008

Declining trends between 1990 and 1996 Incidence rate ~21 per year Mortality rates ~17 per year

Family History Empiric RisksFamily History Empiric RisksLifetime Risk CRC

General population in US ~2 to 6

One 1st degree relative with CRC 2-3 fold

Two 1st degree relatives with CRC 3-4 fold

1st degree relative with CRC lt50 3-4 fold

One 2nd or 3rd degree relative with CRC

~15 fold

Two 2nd degree relatives with CRC 2-3 fold

OutlineOutline Hereditary colorectal cancer syndromes Cancer family history ndash a primary tool Evaluating your patients for familial CRC risk Genetic counseling and testing for hereditary

colorectal cancer How when where to refer patients for genetic

services

Colorectal CancerColorectal Cancer

~5-8 of all cases of CRC are hereditary

~15-20 are ldquofamilialrdquomultifactorial

~75 of cases are sporadic

Characteristics of Average RiskCharacteristics of Average Risk

No well-defined threshold between sporadic and familial CRC at this time

Probably safe to include individuals with No personal risk factors or family history of CRC One 2nd or 3rd degree relative with CRC gt60 years with no

other family history of CRC

Characteristics of ldquoFamilialrdquo CRCCharacteristics of ldquoFamilialrdquo CRC

ldquoClusteringrdquo of colon cancer cases in the family (gt50 at diagnosis) without clear dominant pattern or

One close relative with CRC lt60 years and family history does not meet criteria for known hereditary CRC syndromes

Likely to be multiple low penetrant genes plus environmental factors at play

Family members warrant earlier CRC screening Starting at 40 years or 5-10 years earlier than age of diagnosis

of the youngest affected relative

Characteristics of Hereditary Characteristics of Hereditary CRCCRC

Multiple relatives with colorectal cancer One or more diagnosed at an early age (lt50)

Sequential generations affected Except in autosomal recessive syndromes

Other cancers in the family known to be associated with CRC (uterine ovarian GI)

Multiple primary tumors or polyps

Hereditary CRC SyndromesHereditary CRC Syndromes Hereditary Non-Polyposis Colorectal Cancer (HNPCC)

Variants Muir-Torre Turcot Familial Adenomatous Polyposis (FAP)

Variants Gardner Turcot Attenuated FAP APC mutation in Ashkenazi Jews

Others Multiple adenomatous polyposis syndromeMYH gene (MAP) Peutz-Jeghers syndrome (PJS) Familial Juvenile Polyposis (FJP)

HNPCC AKA ldquoLynch SyndromerdquoHNPCC AKA ldquoLynch Syndromerdquo

2-3 of all colorectal cancer cases Autosomal dominant high penetrance Typical age of CA onset is 40-50 years Multiple affected generations 60-70 right-sidedproximal CRC tumors Polyps may be present multiple primaries

common Can overlap with AFAP

HNPCCHNPCCbull Lifetime cancer risks

ndash Colorectal 80

ndash Endometrial 20-60

ndash Gastric 13-19

ndash Ovarian 9-12

ndash Biliary Tract 2

ndash Urinary Tract 4

ndash Small Bowel 1-4

ndash BrainCNS 1-3

HNPCCHNPCCClinical Diagnostic CriteriaClinical Diagnostic Criteria

Amsterdam II Criteria (3-2-1) 3 or more relatives with an HNPCC-related cancer

one of whom is a 1st degree relative of the other two 2 or more successive generations affected

1 or more cancers diagnosed before age 50

HNPCCHNPCC Caused by mutations or deletions in mismatched

repair (MMR) genes MSH2 MLH1 MSH6 (PMS2)

50 of families meeting Amsterdam II Criteria have detectable mutations

TestingScreening options Direct genetic testing of MMR genes (in select families) Initial screening of the tumor tissue by MSIIHC

MSIIHC ScreeningMSIIHC Screening Microsatellite Instability (MSI) on tumor tissue

can be used to screen for HNPCC in select cases

Immunohistochemistry (IHC) on tumor tissue

can be used to detect the presence or absence of the mismatch repair proteins (MSH2 MLH1 etc)

ldquoScreen positiverdquo individuals can be offered cancer genetic counselingassessment and targeted genetic testing

FAPFAP 1 in 10000 incidence 100rsquos to 1000rsquos of colonic adenomas by teens

Cancer risk colon gastric duodenum (periampulla) small bowel pancreas papillary thyroid childhood hepatoblastoma

7 risk of CRC by 21 yrs 93 by 50 yrs Autosomal dominant APC gene mutations Variants Gardner Turcot

FAP - SurveillanceFAP - Surveillance Colon

Annual sigmoidoscopy age 10-12 yrs Prophylactic colectomy following polyp detection with

continued surveillance of rectum ileal pouch Duodenalgastric

EGD age 25 repeat 1-3 yrs Thyroid

Annual PE age 10 Hepatoblastoma

Annual screen by abd US amp AFP from birth to 5 yrs

Attenuated FAPAttenuated FAP 20 to 100 polyps usually more proximal

Onset later than FAP average AOO = 50 Lifetime risk of CRC = 80

Extracolonic tumors occur at same rate as FAP Variant of FAP mutations in same APC gene Surveillance

annual colonoscopy starting late teens or early 20rsquos Option of subtotal colectomy

Genetic Testing FAPAFAPGenetic Testing FAPAFAP Test an affected family member first

After genetic counseling and informed consent

APC gene testing can confirm a suspected diagnosis

Family members of a person with a known APC mutation can have mutation-specific testing

Genetic testing for children at risk for FAP can be considered before beginning colon screening

APC gene mutation inAPC gene mutation inAshkenazi JewsAshkenazi Jews

Missense mutation (I1307K) associated with increased risk of CRC and adenomas in Ashkenazi Jews (AJ)

Found in 6 of the general AJ population

12 of AJs with CRC

29 of AJs with CRC and a positive family history

Lifetime risk of CRC in mutation carrier is 10-20

Screening colonoscopy every 2-5 yrs starting at 35 yrs

MAP syndromeMYH geneMAP syndromeMYH gene Multiple adenomatous polyposis (MAP) syndrome

Autosomal recessive mutations in the MYH gene Median number of polyps = 55 Mean age of polyp diagnosis = 30-50 years Polyps mainly small mildly dysplastic tubular adenomas Some

tubulovillous hyperplastic serrated adenomas microadenomas

30 of individuals with 15-100 polyps have homozygous mutations in the MYH gene

Genetic testing should be offered if gt15 polyps (and APC gene testing negative)

Peutz-Jeghers SyndromePeutz-Jeghers Syndrome lt1 of all CRC cases Hamartomatous polyps of GI tract as early as 1st decade Mucocutaneous hyper pigmentation

lips mouth buccal mucosa fingers Usually seen in children lt 5 yrs

Cancer risk colon small intestine stomach pancreas breast ovaries uterus testes

lungs kidneys Mutations in STK11 gene

found in 70 of familial cases and 30-70 of sporadic cases

Familial Juvenile PolyposisFamilial Juvenile Polyposis

lt1 of all CRC cases

Autosomal dominant

5 or more juvenile polyps in colon or GI tract

Appear in 1st or 2nd decade

50 lifetime risk of CRC AOO in 30rsquos

Increased risk gastric GI pancreatic CA

~50 of cases have mutations in either the MADH4 or BMPR1A genes

Family Health HistoryFamily Health History

ldquoThe family tree has become the most important genetic test of all The more you know the more tools you have to practice preventive medicinerdquo

Donna Russo Certified Genetic Counselor NY Presbyterian-Columbia Hospital

Goal ClassificationGoal ClassificationAssessment Risk Classification Intervention

Family History

Average

Moderate

(ldquoFamilialrdquo)

HighGenetic

Personalized prevention recommendations

Standard prevention recommendations

Referral for genetic evaluation with personalized prevention recommendations

Consider Genetics Referral forConsider Genetics Referral for

Two or more family members with CRC at least one lt50

Three or more family members wCRC any age

Patient with colon cancer before 40 yrs

Endometrial cancer and family history of CRC lt50

Persons with more than one primary CRC lt50 yrs or with both endometrial CA and CRC

Family or personal history of CRC and one or more 1st degree relative with an HNPCC-related cancer one diagnosed lt50 yrs

Same side of family

Consider Genetics Referral forConsider Genetics Referral for

MSI andor IHC tumor results suspicious for HNPCC

Autosomal dominant pattern of cancers in the family

Persons with 15 or more adenomatous colorectal polyps

Persons with multiple hamartomatous or juvenile GI polyps

Persons with a family history of a known hereditary cancer syndrome

CRC Risk ManagementCRC Risk Management

Average Risk

1 No family history CRC OR2 One 2nd or 3rd degree relative with CRC

FOBT annually + flex sig every 5 years OR Colonoscopy every 10 years OR DCBE every 5 years

Age to Begin50 years

CRC Risk ManagementCRC Risk ManagementModerateFamily history Two 1st degree relatives with CRC any age

or one 1st degree relative with CRC lt 60- Colonoscopy every 5 yrs

One 1st degree relative with CRC gt60 or two 2nd degree relatives with CRC any age- Average risk screening

Or 5-10 yrs earlier than earliest case in family

Age to begin

40 years

40 years

CRC Risk ManagementCRC Risk Management

Age to Begin

HNPCC or suspected HNPCC 20-25 years 1 Colonoscopy every 1-2 yrs

2 Genetic counseling consider genetic testing

FAP or suspected FAP 10-12 years 1 Flex sig or colonoscopy every1-2 yrs

2 Genetic counseling consider genetic testing

Case 1 JoanCase 1 Joan Joan age 38 was recently diagnosed with

endometrial cancer Family history reveals

1 Paternal grandmother endometrial cancer age 50 2 Paternal uncle colon cancer age 48 3 Father colonoscopy at age 50 four adenomatous

polyps removed 4 No other significant history 5 Both sides of the family are Northern European

Caucasian

Pedigree Case 1Pedigree Case 1French Irish Scottish German English

88 yr

61 yr 63 yr

4 polyps

50 yrs 38 yr

35 yrDx 38

8 yr10 yr

CRC Dx 48

Dx 50

KEYKEY

Endometrial CA

Colorectal CA

Adenomatous Polyps

Case 1 AssessmentCase 1 Assessment Joan meets Amsterdam II Criteria and is at risk for HNPCC

Refer to genetics for cancer genetic counseling and discussion of genetic testing for HNPCC

Testing options

1 Direct gene testing of MLH1 and MSH2 OR

2 MSIIHC screening of tumor tissue with gene sequencing if MSI positive

Case 2 TedCase 2 Ted Ted is 30 and wants a colonoscopy because his mother

was just diagnosed with colon cancer after routine screening at age 54 Family history reveals

1 Paternal grandfather died of CRC at age 79

2 No hx of endometrial ovarian small bowel or ureterkidney cancer on either side of family

3 Two maternal aunts cervical cancer at ages 30 amp 34

4 Maternal grandmother breast cancer age 85

Pedigree Case 2Pedigree Case 2Italian Irish German

KEY

CRC

Breast CA

Cervical CA

84

d 58 MIBrCa 85 yrs

d87

55 58 60

Colon CA 54 yrs

Cervical CA 30 yrs

Cervical CA 32 yrs

34 yrs 30 yrs

CRC 79 d82

56

Case 2 TedCase 2 Ted Verify Diagnoses Obtain and review pathology reports on

all reported cancers whenever possible

If diagnoses are correct Ted has no family history indicative of a known colon cancer syndrome (HNPCC FAP other)

Tedrsquos lifetime risk of colorectal CA is increased 2 to 3 fold due to one affected first degree relative (gt50)

Moderatefamilial risk Screening by colonoscopy starting at age 40 or 10 yrs earlier than earliest case in family is reasonable

Chemo PreventionChemo Prevention Evidence that ASA NSAIDs Calcium and COX-2

inhibitors may reduce incidence of CA by reducing ofadenomas

1048707 40-50 risk reduction for developing colorectal CA regardless of location in colon age gender and race

Generally performed by RCTrsquos in patients with priorcolorectal CA followed for recurrence of adenomas

Diet fiber and antioxidant vitamins have not beenshown by RCTrsquos to decrease risk of recurrent adenomas

COX-2irsquos and Sulindac have been shown to reduce thenumber of adenomas found in FAP alone

1048707 Not effective for sporadic colon CA 1048707 Actually can cause regression of adenomas

Adenoma-Carcinoma SequenceAdenoma-Carcinoma SequenceAccumulation of MutationsAccumulation of Mutations

DCC MCC p53 K-ras APC MSH2 MLH1 etcDCC MCC p53 K-ras APC MSH2 MLH1 etc

Estimated New Cancer Cases of 10 Estimated New Cancer Cases of 10 Leading Sites by Gender for the US 2000Leading Sites by Gender for the US 2000

MaleProstate 29

Lung and bronchus 14

Colon and rectum 10

Urinary bladder 6

Non-Hodgkinrsquos Lymphoma 5

Melanoma of skin 4

Oral cavity and pharynx 3

Kidney and renal pelvis 3

Leukemia 2

Pancreas 2

All other sites 19

FemaleProstate 30

Lung and bronchus 12

Colon and rectum 11

Urinary bladder 6

Non-Hodgkinrsquos Lymphoma 4

Melanoma of skin 4

Oral cavity and pharynx 3

Kidney and renal pelvis 2

Leukemia 2

Pancreas 2

All other sites 22

Average Annual Age-Specific US Average Annual Age-Specific US Incidence and Mortality Rates of CRC Incidence and Mortality Rates of CRC

1992-19961992-1996

Prevalence of Adenomas and Prevalence of Adenomas and Incidence of Colon CancerIncidence of Colon Cancer

Age gt50 years with any adenomas 25-40

Lifetime risk of cancer at age 50 years 5 for females 6 for males

Persons with advanced adenomas are at greatest risk

Risk Factors for Colorectal Cancer Risk Factors for Colorectal Cancer (CRC)(CRC)

Aging Personal history of CRC or adenomas High-fat low-fiber diet Inflammatory bowel disease Family history of CRC Hereditary colon cancer syndromes

Risk of Colorectal Cancer Risk of Colorectal Cancer (CRC)(CRC)

0 20 40 60 80 100

Personal History of Colorectal Neoplasia

General Population

Inflammatory Bowel Disease

Familial Adenomatous Polyposis

(FAP)

HNPCC Mutation

Lifetime Risk ()

5

15-20

15-40

70-80

gt95

Colorectal CancerColorectal CancerStatistics in the USStatistics in the US

Second overall leading cause of cancer-related deaths in the US

Estimated 149000 new cases and 50000 deaths in the year 2008

Declining trends between 1990 and 1996 Incidence rate ~21 per year Mortality rates ~17 per year

Family History Empiric RisksFamily History Empiric RisksLifetime Risk CRC

General population in US ~2 to 6

One 1st degree relative with CRC 2-3 fold

Two 1st degree relatives with CRC 3-4 fold

1st degree relative with CRC lt50 3-4 fold

One 2nd or 3rd degree relative with CRC

~15 fold

Two 2nd degree relatives with CRC 2-3 fold

OutlineOutline Hereditary colorectal cancer syndromes Cancer family history ndash a primary tool Evaluating your patients for familial CRC risk Genetic counseling and testing for hereditary

colorectal cancer How when where to refer patients for genetic

services

Colorectal CancerColorectal Cancer

~5-8 of all cases of CRC are hereditary

~15-20 are ldquofamilialrdquomultifactorial

~75 of cases are sporadic

Characteristics of Average RiskCharacteristics of Average Risk

No well-defined threshold between sporadic and familial CRC at this time

Probably safe to include individuals with No personal risk factors or family history of CRC One 2nd or 3rd degree relative with CRC gt60 years with no

other family history of CRC

Characteristics of ldquoFamilialrdquo CRCCharacteristics of ldquoFamilialrdquo CRC

ldquoClusteringrdquo of colon cancer cases in the family (gt50 at diagnosis) without clear dominant pattern or

One close relative with CRC lt60 years and family history does not meet criteria for known hereditary CRC syndromes

Likely to be multiple low penetrant genes plus environmental factors at play

Family members warrant earlier CRC screening Starting at 40 years or 5-10 years earlier than age of diagnosis

of the youngest affected relative

Characteristics of Hereditary Characteristics of Hereditary CRCCRC

Multiple relatives with colorectal cancer One or more diagnosed at an early age (lt50)

Sequential generations affected Except in autosomal recessive syndromes

Other cancers in the family known to be associated with CRC (uterine ovarian GI)

Multiple primary tumors or polyps

Hereditary CRC SyndromesHereditary CRC Syndromes Hereditary Non-Polyposis Colorectal Cancer (HNPCC)

Variants Muir-Torre Turcot Familial Adenomatous Polyposis (FAP)

Variants Gardner Turcot Attenuated FAP APC mutation in Ashkenazi Jews

Others Multiple adenomatous polyposis syndromeMYH gene (MAP) Peutz-Jeghers syndrome (PJS) Familial Juvenile Polyposis (FJP)

HNPCC AKA ldquoLynch SyndromerdquoHNPCC AKA ldquoLynch Syndromerdquo

2-3 of all colorectal cancer cases Autosomal dominant high penetrance Typical age of CA onset is 40-50 years Multiple affected generations 60-70 right-sidedproximal CRC tumors Polyps may be present multiple primaries

common Can overlap with AFAP

HNPCCHNPCCbull Lifetime cancer risks

ndash Colorectal 80

ndash Endometrial 20-60

ndash Gastric 13-19

ndash Ovarian 9-12

ndash Biliary Tract 2

ndash Urinary Tract 4

ndash Small Bowel 1-4

ndash BrainCNS 1-3

HNPCCHNPCCClinical Diagnostic CriteriaClinical Diagnostic Criteria

Amsterdam II Criteria (3-2-1) 3 or more relatives with an HNPCC-related cancer

one of whom is a 1st degree relative of the other two 2 or more successive generations affected

1 or more cancers diagnosed before age 50

HNPCCHNPCC Caused by mutations or deletions in mismatched

repair (MMR) genes MSH2 MLH1 MSH6 (PMS2)

50 of families meeting Amsterdam II Criteria have detectable mutations

TestingScreening options Direct genetic testing of MMR genes (in select families) Initial screening of the tumor tissue by MSIIHC

MSIIHC ScreeningMSIIHC Screening Microsatellite Instability (MSI) on tumor tissue

can be used to screen for HNPCC in select cases

Immunohistochemistry (IHC) on tumor tissue

can be used to detect the presence or absence of the mismatch repair proteins (MSH2 MLH1 etc)

ldquoScreen positiverdquo individuals can be offered cancer genetic counselingassessment and targeted genetic testing

FAPFAP 1 in 10000 incidence 100rsquos to 1000rsquos of colonic adenomas by teens

Cancer risk colon gastric duodenum (periampulla) small bowel pancreas papillary thyroid childhood hepatoblastoma

7 risk of CRC by 21 yrs 93 by 50 yrs Autosomal dominant APC gene mutations Variants Gardner Turcot

FAP - SurveillanceFAP - Surveillance Colon

Annual sigmoidoscopy age 10-12 yrs Prophylactic colectomy following polyp detection with

continued surveillance of rectum ileal pouch Duodenalgastric

EGD age 25 repeat 1-3 yrs Thyroid

Annual PE age 10 Hepatoblastoma

Annual screen by abd US amp AFP from birth to 5 yrs

Attenuated FAPAttenuated FAP 20 to 100 polyps usually more proximal

Onset later than FAP average AOO = 50 Lifetime risk of CRC = 80

Extracolonic tumors occur at same rate as FAP Variant of FAP mutations in same APC gene Surveillance

annual colonoscopy starting late teens or early 20rsquos Option of subtotal colectomy

Genetic Testing FAPAFAPGenetic Testing FAPAFAP Test an affected family member first

After genetic counseling and informed consent

APC gene testing can confirm a suspected diagnosis

Family members of a person with a known APC mutation can have mutation-specific testing

Genetic testing for children at risk for FAP can be considered before beginning colon screening

APC gene mutation inAPC gene mutation inAshkenazi JewsAshkenazi Jews

Missense mutation (I1307K) associated with increased risk of CRC and adenomas in Ashkenazi Jews (AJ)

Found in 6 of the general AJ population

12 of AJs with CRC

29 of AJs with CRC and a positive family history

Lifetime risk of CRC in mutation carrier is 10-20

Screening colonoscopy every 2-5 yrs starting at 35 yrs

MAP syndromeMYH geneMAP syndromeMYH gene Multiple adenomatous polyposis (MAP) syndrome

Autosomal recessive mutations in the MYH gene Median number of polyps = 55 Mean age of polyp diagnosis = 30-50 years Polyps mainly small mildly dysplastic tubular adenomas Some

tubulovillous hyperplastic serrated adenomas microadenomas

30 of individuals with 15-100 polyps have homozygous mutations in the MYH gene

Genetic testing should be offered if gt15 polyps (and APC gene testing negative)

Peutz-Jeghers SyndromePeutz-Jeghers Syndrome lt1 of all CRC cases Hamartomatous polyps of GI tract as early as 1st decade Mucocutaneous hyper pigmentation

lips mouth buccal mucosa fingers Usually seen in children lt 5 yrs

Cancer risk colon small intestine stomach pancreas breast ovaries uterus testes

lungs kidneys Mutations in STK11 gene

found in 70 of familial cases and 30-70 of sporadic cases

Familial Juvenile PolyposisFamilial Juvenile Polyposis

lt1 of all CRC cases

Autosomal dominant

5 or more juvenile polyps in colon or GI tract

Appear in 1st or 2nd decade

50 lifetime risk of CRC AOO in 30rsquos

Increased risk gastric GI pancreatic CA

~50 of cases have mutations in either the MADH4 or BMPR1A genes

Family Health HistoryFamily Health History

ldquoThe family tree has become the most important genetic test of all The more you know the more tools you have to practice preventive medicinerdquo

Donna Russo Certified Genetic Counselor NY Presbyterian-Columbia Hospital

Goal ClassificationGoal ClassificationAssessment Risk Classification Intervention

Family History

Average

Moderate

(ldquoFamilialrdquo)

HighGenetic

Personalized prevention recommendations

Standard prevention recommendations

Referral for genetic evaluation with personalized prevention recommendations

Consider Genetics Referral forConsider Genetics Referral for

Two or more family members with CRC at least one lt50

Three or more family members wCRC any age

Patient with colon cancer before 40 yrs

Endometrial cancer and family history of CRC lt50

Persons with more than one primary CRC lt50 yrs or with both endometrial CA and CRC

Family or personal history of CRC and one or more 1st degree relative with an HNPCC-related cancer one diagnosed lt50 yrs

Same side of family

Consider Genetics Referral forConsider Genetics Referral for

MSI andor IHC tumor results suspicious for HNPCC

Autosomal dominant pattern of cancers in the family

Persons with 15 or more adenomatous colorectal polyps

Persons with multiple hamartomatous or juvenile GI polyps

Persons with a family history of a known hereditary cancer syndrome

CRC Risk ManagementCRC Risk Management

Average Risk

1 No family history CRC OR2 One 2nd or 3rd degree relative with CRC

FOBT annually + flex sig every 5 years OR Colonoscopy every 10 years OR DCBE every 5 years

Age to Begin50 years

CRC Risk ManagementCRC Risk ManagementModerateFamily history Two 1st degree relatives with CRC any age

or one 1st degree relative with CRC lt 60- Colonoscopy every 5 yrs

One 1st degree relative with CRC gt60 or two 2nd degree relatives with CRC any age- Average risk screening

Or 5-10 yrs earlier than earliest case in family

Age to begin

40 years

40 years

CRC Risk ManagementCRC Risk Management

Age to Begin

HNPCC or suspected HNPCC 20-25 years 1 Colonoscopy every 1-2 yrs

2 Genetic counseling consider genetic testing

FAP or suspected FAP 10-12 years 1 Flex sig or colonoscopy every1-2 yrs

2 Genetic counseling consider genetic testing

Case 1 JoanCase 1 Joan Joan age 38 was recently diagnosed with

endometrial cancer Family history reveals

1 Paternal grandmother endometrial cancer age 50 2 Paternal uncle colon cancer age 48 3 Father colonoscopy at age 50 four adenomatous

polyps removed 4 No other significant history 5 Both sides of the family are Northern European

Caucasian

Pedigree Case 1Pedigree Case 1French Irish Scottish German English

88 yr

61 yr 63 yr

4 polyps

50 yrs 38 yr

35 yrDx 38

8 yr10 yr

CRC Dx 48

Dx 50

KEYKEY

Endometrial CA

Colorectal CA

Adenomatous Polyps

Case 1 AssessmentCase 1 Assessment Joan meets Amsterdam II Criteria and is at risk for HNPCC

Refer to genetics for cancer genetic counseling and discussion of genetic testing for HNPCC

Testing options

1 Direct gene testing of MLH1 and MSH2 OR

2 MSIIHC screening of tumor tissue with gene sequencing if MSI positive

Case 2 TedCase 2 Ted Ted is 30 and wants a colonoscopy because his mother

was just diagnosed with colon cancer after routine screening at age 54 Family history reveals

1 Paternal grandfather died of CRC at age 79

2 No hx of endometrial ovarian small bowel or ureterkidney cancer on either side of family

3 Two maternal aunts cervical cancer at ages 30 amp 34

4 Maternal grandmother breast cancer age 85

Pedigree Case 2Pedigree Case 2Italian Irish German

KEY

CRC

Breast CA

Cervical CA

84

d 58 MIBrCa 85 yrs

d87

55 58 60

Colon CA 54 yrs

Cervical CA 30 yrs

Cervical CA 32 yrs

34 yrs 30 yrs

CRC 79 d82

56

Case 2 TedCase 2 Ted Verify Diagnoses Obtain and review pathology reports on

all reported cancers whenever possible

If diagnoses are correct Ted has no family history indicative of a known colon cancer syndrome (HNPCC FAP other)

Tedrsquos lifetime risk of colorectal CA is increased 2 to 3 fold due to one affected first degree relative (gt50)

Moderatefamilial risk Screening by colonoscopy starting at age 40 or 10 yrs earlier than earliest case in family is reasonable

Chemo PreventionChemo Prevention Evidence that ASA NSAIDs Calcium and COX-2

inhibitors may reduce incidence of CA by reducing ofadenomas

1048707 40-50 risk reduction for developing colorectal CA regardless of location in colon age gender and race

Generally performed by RCTrsquos in patients with priorcolorectal CA followed for recurrence of adenomas

Diet fiber and antioxidant vitamins have not beenshown by RCTrsquos to decrease risk of recurrent adenomas

COX-2irsquos and Sulindac have been shown to reduce thenumber of adenomas found in FAP alone

1048707 Not effective for sporadic colon CA 1048707 Actually can cause regression of adenomas

Estimated New Cancer Cases of 10 Estimated New Cancer Cases of 10 Leading Sites by Gender for the US 2000Leading Sites by Gender for the US 2000

MaleProstate 29

Lung and bronchus 14

Colon and rectum 10

Urinary bladder 6

Non-Hodgkinrsquos Lymphoma 5

Melanoma of skin 4

Oral cavity and pharynx 3

Kidney and renal pelvis 3

Leukemia 2

Pancreas 2

All other sites 19

FemaleProstate 30

Lung and bronchus 12

Colon and rectum 11

Urinary bladder 6

Non-Hodgkinrsquos Lymphoma 4

Melanoma of skin 4

Oral cavity and pharynx 3

Kidney and renal pelvis 2

Leukemia 2

Pancreas 2

All other sites 22

Average Annual Age-Specific US Average Annual Age-Specific US Incidence and Mortality Rates of CRC Incidence and Mortality Rates of CRC

1992-19961992-1996

Prevalence of Adenomas and Prevalence of Adenomas and Incidence of Colon CancerIncidence of Colon Cancer

Age gt50 years with any adenomas 25-40

Lifetime risk of cancer at age 50 years 5 for females 6 for males

Persons with advanced adenomas are at greatest risk

Risk Factors for Colorectal Cancer Risk Factors for Colorectal Cancer (CRC)(CRC)

Aging Personal history of CRC or adenomas High-fat low-fiber diet Inflammatory bowel disease Family history of CRC Hereditary colon cancer syndromes

Risk of Colorectal Cancer Risk of Colorectal Cancer (CRC)(CRC)

0 20 40 60 80 100

Personal History of Colorectal Neoplasia

General Population

Inflammatory Bowel Disease

Familial Adenomatous Polyposis

(FAP)

HNPCC Mutation

Lifetime Risk ()

5

15-20

15-40

70-80

gt95

Colorectal CancerColorectal CancerStatistics in the USStatistics in the US

Second overall leading cause of cancer-related deaths in the US

Estimated 149000 new cases and 50000 deaths in the year 2008

Declining trends between 1990 and 1996 Incidence rate ~21 per year Mortality rates ~17 per year

Family History Empiric RisksFamily History Empiric RisksLifetime Risk CRC

General population in US ~2 to 6

One 1st degree relative with CRC 2-3 fold

Two 1st degree relatives with CRC 3-4 fold

1st degree relative with CRC lt50 3-4 fold

One 2nd or 3rd degree relative with CRC

~15 fold

Two 2nd degree relatives with CRC 2-3 fold

OutlineOutline Hereditary colorectal cancer syndromes Cancer family history ndash a primary tool Evaluating your patients for familial CRC risk Genetic counseling and testing for hereditary

colorectal cancer How when where to refer patients for genetic

services

Colorectal CancerColorectal Cancer

~5-8 of all cases of CRC are hereditary

~15-20 are ldquofamilialrdquomultifactorial

~75 of cases are sporadic

Characteristics of Average RiskCharacteristics of Average Risk

No well-defined threshold between sporadic and familial CRC at this time

Probably safe to include individuals with No personal risk factors or family history of CRC One 2nd or 3rd degree relative with CRC gt60 years with no

other family history of CRC

Characteristics of ldquoFamilialrdquo CRCCharacteristics of ldquoFamilialrdquo CRC

ldquoClusteringrdquo of colon cancer cases in the family (gt50 at diagnosis) without clear dominant pattern or

One close relative with CRC lt60 years and family history does not meet criteria for known hereditary CRC syndromes

Likely to be multiple low penetrant genes plus environmental factors at play

Family members warrant earlier CRC screening Starting at 40 years or 5-10 years earlier than age of diagnosis

of the youngest affected relative

Characteristics of Hereditary Characteristics of Hereditary CRCCRC

Multiple relatives with colorectal cancer One or more diagnosed at an early age (lt50)

Sequential generations affected Except in autosomal recessive syndromes

Other cancers in the family known to be associated with CRC (uterine ovarian GI)

Multiple primary tumors or polyps

Hereditary CRC SyndromesHereditary CRC Syndromes Hereditary Non-Polyposis Colorectal Cancer (HNPCC)

Variants Muir-Torre Turcot Familial Adenomatous Polyposis (FAP)

Variants Gardner Turcot Attenuated FAP APC mutation in Ashkenazi Jews

Others Multiple adenomatous polyposis syndromeMYH gene (MAP) Peutz-Jeghers syndrome (PJS) Familial Juvenile Polyposis (FJP)

HNPCC AKA ldquoLynch SyndromerdquoHNPCC AKA ldquoLynch Syndromerdquo

2-3 of all colorectal cancer cases Autosomal dominant high penetrance Typical age of CA onset is 40-50 years Multiple affected generations 60-70 right-sidedproximal CRC tumors Polyps may be present multiple primaries

common Can overlap with AFAP

HNPCCHNPCCbull Lifetime cancer risks

ndash Colorectal 80

ndash Endometrial 20-60

ndash Gastric 13-19

ndash Ovarian 9-12

ndash Biliary Tract 2

ndash Urinary Tract 4

ndash Small Bowel 1-4

ndash BrainCNS 1-3

HNPCCHNPCCClinical Diagnostic CriteriaClinical Diagnostic Criteria

Amsterdam II Criteria (3-2-1) 3 or more relatives with an HNPCC-related cancer

one of whom is a 1st degree relative of the other two 2 or more successive generations affected

1 or more cancers diagnosed before age 50

HNPCCHNPCC Caused by mutations or deletions in mismatched

repair (MMR) genes MSH2 MLH1 MSH6 (PMS2)

50 of families meeting Amsterdam II Criteria have detectable mutations

TestingScreening options Direct genetic testing of MMR genes (in select families) Initial screening of the tumor tissue by MSIIHC

MSIIHC ScreeningMSIIHC Screening Microsatellite Instability (MSI) on tumor tissue

can be used to screen for HNPCC in select cases

Immunohistochemistry (IHC) on tumor tissue

can be used to detect the presence or absence of the mismatch repair proteins (MSH2 MLH1 etc)

ldquoScreen positiverdquo individuals can be offered cancer genetic counselingassessment and targeted genetic testing

FAPFAP 1 in 10000 incidence 100rsquos to 1000rsquos of colonic adenomas by teens

Cancer risk colon gastric duodenum (periampulla) small bowel pancreas papillary thyroid childhood hepatoblastoma

7 risk of CRC by 21 yrs 93 by 50 yrs Autosomal dominant APC gene mutations Variants Gardner Turcot

FAP - SurveillanceFAP - Surveillance Colon

Annual sigmoidoscopy age 10-12 yrs Prophylactic colectomy following polyp detection with

continued surveillance of rectum ileal pouch Duodenalgastric

EGD age 25 repeat 1-3 yrs Thyroid

Annual PE age 10 Hepatoblastoma

Annual screen by abd US amp AFP from birth to 5 yrs

Attenuated FAPAttenuated FAP 20 to 100 polyps usually more proximal

Onset later than FAP average AOO = 50 Lifetime risk of CRC = 80

Extracolonic tumors occur at same rate as FAP Variant of FAP mutations in same APC gene Surveillance

annual colonoscopy starting late teens or early 20rsquos Option of subtotal colectomy

Genetic Testing FAPAFAPGenetic Testing FAPAFAP Test an affected family member first

After genetic counseling and informed consent

APC gene testing can confirm a suspected diagnosis

Family members of a person with a known APC mutation can have mutation-specific testing

Genetic testing for children at risk for FAP can be considered before beginning colon screening

APC gene mutation inAPC gene mutation inAshkenazi JewsAshkenazi Jews

Missense mutation (I1307K) associated with increased risk of CRC and adenomas in Ashkenazi Jews (AJ)

Found in 6 of the general AJ population

12 of AJs with CRC

29 of AJs with CRC and a positive family history

Lifetime risk of CRC in mutation carrier is 10-20

Screening colonoscopy every 2-5 yrs starting at 35 yrs

MAP syndromeMYH geneMAP syndromeMYH gene Multiple adenomatous polyposis (MAP) syndrome

Autosomal recessive mutations in the MYH gene Median number of polyps = 55 Mean age of polyp diagnosis = 30-50 years Polyps mainly small mildly dysplastic tubular adenomas Some

tubulovillous hyperplastic serrated adenomas microadenomas

30 of individuals with 15-100 polyps have homozygous mutations in the MYH gene

Genetic testing should be offered if gt15 polyps (and APC gene testing negative)

Peutz-Jeghers SyndromePeutz-Jeghers Syndrome lt1 of all CRC cases Hamartomatous polyps of GI tract as early as 1st decade Mucocutaneous hyper pigmentation

lips mouth buccal mucosa fingers Usually seen in children lt 5 yrs

Cancer risk colon small intestine stomach pancreas breast ovaries uterus testes

lungs kidneys Mutations in STK11 gene

found in 70 of familial cases and 30-70 of sporadic cases

Familial Juvenile PolyposisFamilial Juvenile Polyposis

lt1 of all CRC cases

Autosomal dominant

5 or more juvenile polyps in colon or GI tract

Appear in 1st or 2nd decade

50 lifetime risk of CRC AOO in 30rsquos

Increased risk gastric GI pancreatic CA

~50 of cases have mutations in either the MADH4 or BMPR1A genes

Family Health HistoryFamily Health History

ldquoThe family tree has become the most important genetic test of all The more you know the more tools you have to practice preventive medicinerdquo

Donna Russo Certified Genetic Counselor NY Presbyterian-Columbia Hospital

Goal ClassificationGoal ClassificationAssessment Risk Classification Intervention

Family History

Average

Moderate

(ldquoFamilialrdquo)

HighGenetic

Personalized prevention recommendations

Standard prevention recommendations

Referral for genetic evaluation with personalized prevention recommendations

Consider Genetics Referral forConsider Genetics Referral for

Two or more family members with CRC at least one lt50

Three or more family members wCRC any age

Patient with colon cancer before 40 yrs

Endometrial cancer and family history of CRC lt50

Persons with more than one primary CRC lt50 yrs or with both endometrial CA and CRC

Family or personal history of CRC and one or more 1st degree relative with an HNPCC-related cancer one diagnosed lt50 yrs

Same side of family

Consider Genetics Referral forConsider Genetics Referral for

MSI andor IHC tumor results suspicious for HNPCC

Autosomal dominant pattern of cancers in the family

Persons with 15 or more adenomatous colorectal polyps

Persons with multiple hamartomatous or juvenile GI polyps

Persons with a family history of a known hereditary cancer syndrome

CRC Risk ManagementCRC Risk Management

Average Risk

1 No family history CRC OR2 One 2nd or 3rd degree relative with CRC

FOBT annually + flex sig every 5 years OR Colonoscopy every 10 years OR DCBE every 5 years

Age to Begin50 years

CRC Risk ManagementCRC Risk ManagementModerateFamily history Two 1st degree relatives with CRC any age

or one 1st degree relative with CRC lt 60- Colonoscopy every 5 yrs

One 1st degree relative with CRC gt60 or two 2nd degree relatives with CRC any age- Average risk screening

Or 5-10 yrs earlier than earliest case in family

Age to begin

40 years

40 years

CRC Risk ManagementCRC Risk Management

Age to Begin

HNPCC or suspected HNPCC 20-25 years 1 Colonoscopy every 1-2 yrs

2 Genetic counseling consider genetic testing

FAP or suspected FAP 10-12 years 1 Flex sig or colonoscopy every1-2 yrs

2 Genetic counseling consider genetic testing

Case 1 JoanCase 1 Joan Joan age 38 was recently diagnosed with

endometrial cancer Family history reveals

1 Paternal grandmother endometrial cancer age 50 2 Paternal uncle colon cancer age 48 3 Father colonoscopy at age 50 four adenomatous

polyps removed 4 No other significant history 5 Both sides of the family are Northern European

Caucasian

Pedigree Case 1Pedigree Case 1French Irish Scottish German English

88 yr

61 yr 63 yr

4 polyps

50 yrs 38 yr

35 yrDx 38

8 yr10 yr

CRC Dx 48

Dx 50

KEYKEY

Endometrial CA

Colorectal CA

Adenomatous Polyps

Case 1 AssessmentCase 1 Assessment Joan meets Amsterdam II Criteria and is at risk for HNPCC

Refer to genetics for cancer genetic counseling and discussion of genetic testing for HNPCC

Testing options

1 Direct gene testing of MLH1 and MSH2 OR

2 MSIIHC screening of tumor tissue with gene sequencing if MSI positive

Case 2 TedCase 2 Ted Ted is 30 and wants a colonoscopy because his mother

was just diagnosed with colon cancer after routine screening at age 54 Family history reveals

1 Paternal grandfather died of CRC at age 79

2 No hx of endometrial ovarian small bowel or ureterkidney cancer on either side of family

3 Two maternal aunts cervical cancer at ages 30 amp 34

4 Maternal grandmother breast cancer age 85

Pedigree Case 2Pedigree Case 2Italian Irish German

KEY

CRC

Breast CA

Cervical CA

84

d 58 MIBrCa 85 yrs

d87

55 58 60

Colon CA 54 yrs

Cervical CA 30 yrs

Cervical CA 32 yrs

34 yrs 30 yrs

CRC 79 d82

56

Case 2 TedCase 2 Ted Verify Diagnoses Obtain and review pathology reports on

all reported cancers whenever possible

If diagnoses are correct Ted has no family history indicative of a known colon cancer syndrome (HNPCC FAP other)

Tedrsquos lifetime risk of colorectal CA is increased 2 to 3 fold due to one affected first degree relative (gt50)

Moderatefamilial risk Screening by colonoscopy starting at age 40 or 10 yrs earlier than earliest case in family is reasonable

Chemo PreventionChemo Prevention Evidence that ASA NSAIDs Calcium and COX-2

inhibitors may reduce incidence of CA by reducing ofadenomas

1048707 40-50 risk reduction for developing colorectal CA regardless of location in colon age gender and race

Generally performed by RCTrsquos in patients with priorcolorectal CA followed for recurrence of adenomas

Diet fiber and antioxidant vitamins have not beenshown by RCTrsquos to decrease risk of recurrent adenomas

COX-2irsquos and Sulindac have been shown to reduce thenumber of adenomas found in FAP alone

1048707 Not effective for sporadic colon CA 1048707 Actually can cause regression of adenomas

Average Annual Age-Specific US Average Annual Age-Specific US Incidence and Mortality Rates of CRC Incidence and Mortality Rates of CRC

1992-19961992-1996

Prevalence of Adenomas and Prevalence of Adenomas and Incidence of Colon CancerIncidence of Colon Cancer

Age gt50 years with any adenomas 25-40

Lifetime risk of cancer at age 50 years 5 for females 6 for males

Persons with advanced adenomas are at greatest risk

Risk Factors for Colorectal Cancer Risk Factors for Colorectal Cancer (CRC)(CRC)

Aging Personal history of CRC or adenomas High-fat low-fiber diet Inflammatory bowel disease Family history of CRC Hereditary colon cancer syndromes

Risk of Colorectal Cancer Risk of Colorectal Cancer (CRC)(CRC)

0 20 40 60 80 100

Personal History of Colorectal Neoplasia

General Population

Inflammatory Bowel Disease

Familial Adenomatous Polyposis

(FAP)

HNPCC Mutation

Lifetime Risk ()

5

15-20

15-40

70-80

gt95

Colorectal CancerColorectal CancerStatistics in the USStatistics in the US

Second overall leading cause of cancer-related deaths in the US

Estimated 149000 new cases and 50000 deaths in the year 2008

Declining trends between 1990 and 1996 Incidence rate ~21 per year Mortality rates ~17 per year

Family History Empiric RisksFamily History Empiric RisksLifetime Risk CRC

General population in US ~2 to 6

One 1st degree relative with CRC 2-3 fold

Two 1st degree relatives with CRC 3-4 fold

1st degree relative with CRC lt50 3-4 fold

One 2nd or 3rd degree relative with CRC

~15 fold

Two 2nd degree relatives with CRC 2-3 fold

OutlineOutline Hereditary colorectal cancer syndromes Cancer family history ndash a primary tool Evaluating your patients for familial CRC risk Genetic counseling and testing for hereditary

colorectal cancer How when where to refer patients for genetic

services

Colorectal CancerColorectal Cancer

~5-8 of all cases of CRC are hereditary

~15-20 are ldquofamilialrdquomultifactorial

~75 of cases are sporadic

Characteristics of Average RiskCharacteristics of Average Risk

No well-defined threshold between sporadic and familial CRC at this time

Probably safe to include individuals with No personal risk factors or family history of CRC One 2nd or 3rd degree relative with CRC gt60 years with no

other family history of CRC

Characteristics of ldquoFamilialrdquo CRCCharacteristics of ldquoFamilialrdquo CRC

ldquoClusteringrdquo of colon cancer cases in the family (gt50 at diagnosis) without clear dominant pattern or

One close relative with CRC lt60 years and family history does not meet criteria for known hereditary CRC syndromes

Likely to be multiple low penetrant genes plus environmental factors at play

Family members warrant earlier CRC screening Starting at 40 years or 5-10 years earlier than age of diagnosis

of the youngest affected relative

Characteristics of Hereditary Characteristics of Hereditary CRCCRC

Multiple relatives with colorectal cancer One or more diagnosed at an early age (lt50)

Sequential generations affected Except in autosomal recessive syndromes

Other cancers in the family known to be associated with CRC (uterine ovarian GI)

Multiple primary tumors or polyps

Hereditary CRC SyndromesHereditary CRC Syndromes Hereditary Non-Polyposis Colorectal Cancer (HNPCC)

Variants Muir-Torre Turcot Familial Adenomatous Polyposis (FAP)

Variants Gardner Turcot Attenuated FAP APC mutation in Ashkenazi Jews

Others Multiple adenomatous polyposis syndromeMYH gene (MAP) Peutz-Jeghers syndrome (PJS) Familial Juvenile Polyposis (FJP)

HNPCC AKA ldquoLynch SyndromerdquoHNPCC AKA ldquoLynch Syndromerdquo

2-3 of all colorectal cancer cases Autosomal dominant high penetrance Typical age of CA onset is 40-50 years Multiple affected generations 60-70 right-sidedproximal CRC tumors Polyps may be present multiple primaries

common Can overlap with AFAP

HNPCCHNPCCbull Lifetime cancer risks

ndash Colorectal 80

ndash Endometrial 20-60

ndash Gastric 13-19

ndash Ovarian 9-12

ndash Biliary Tract 2

ndash Urinary Tract 4

ndash Small Bowel 1-4

ndash BrainCNS 1-3

HNPCCHNPCCClinical Diagnostic CriteriaClinical Diagnostic Criteria

Amsterdam II Criteria (3-2-1) 3 or more relatives with an HNPCC-related cancer

one of whom is a 1st degree relative of the other two 2 or more successive generations affected

1 or more cancers diagnosed before age 50

HNPCCHNPCC Caused by mutations or deletions in mismatched

repair (MMR) genes MSH2 MLH1 MSH6 (PMS2)

50 of families meeting Amsterdam II Criteria have detectable mutations

TestingScreening options Direct genetic testing of MMR genes (in select families) Initial screening of the tumor tissue by MSIIHC

MSIIHC ScreeningMSIIHC Screening Microsatellite Instability (MSI) on tumor tissue

can be used to screen for HNPCC in select cases

Immunohistochemistry (IHC) on tumor tissue

can be used to detect the presence or absence of the mismatch repair proteins (MSH2 MLH1 etc)

ldquoScreen positiverdquo individuals can be offered cancer genetic counselingassessment and targeted genetic testing

FAPFAP 1 in 10000 incidence 100rsquos to 1000rsquos of colonic adenomas by teens

Cancer risk colon gastric duodenum (periampulla) small bowel pancreas papillary thyroid childhood hepatoblastoma

7 risk of CRC by 21 yrs 93 by 50 yrs Autosomal dominant APC gene mutations Variants Gardner Turcot

FAP - SurveillanceFAP - Surveillance Colon

Annual sigmoidoscopy age 10-12 yrs Prophylactic colectomy following polyp detection with

continued surveillance of rectum ileal pouch Duodenalgastric

EGD age 25 repeat 1-3 yrs Thyroid

Annual PE age 10 Hepatoblastoma

Annual screen by abd US amp AFP from birth to 5 yrs

Attenuated FAPAttenuated FAP 20 to 100 polyps usually more proximal

Onset later than FAP average AOO = 50 Lifetime risk of CRC = 80

Extracolonic tumors occur at same rate as FAP Variant of FAP mutations in same APC gene Surveillance

annual colonoscopy starting late teens or early 20rsquos Option of subtotal colectomy

Genetic Testing FAPAFAPGenetic Testing FAPAFAP Test an affected family member first

After genetic counseling and informed consent

APC gene testing can confirm a suspected diagnosis

Family members of a person with a known APC mutation can have mutation-specific testing

Genetic testing for children at risk for FAP can be considered before beginning colon screening

APC gene mutation inAPC gene mutation inAshkenazi JewsAshkenazi Jews

Missense mutation (I1307K) associated with increased risk of CRC and adenomas in Ashkenazi Jews (AJ)

Found in 6 of the general AJ population

12 of AJs with CRC

29 of AJs with CRC and a positive family history

Lifetime risk of CRC in mutation carrier is 10-20

Screening colonoscopy every 2-5 yrs starting at 35 yrs

MAP syndromeMYH geneMAP syndromeMYH gene Multiple adenomatous polyposis (MAP) syndrome

Autosomal recessive mutations in the MYH gene Median number of polyps = 55 Mean age of polyp diagnosis = 30-50 years Polyps mainly small mildly dysplastic tubular adenomas Some

tubulovillous hyperplastic serrated adenomas microadenomas

30 of individuals with 15-100 polyps have homozygous mutations in the MYH gene

Genetic testing should be offered if gt15 polyps (and APC gene testing negative)

Peutz-Jeghers SyndromePeutz-Jeghers Syndrome lt1 of all CRC cases Hamartomatous polyps of GI tract as early as 1st decade Mucocutaneous hyper pigmentation

lips mouth buccal mucosa fingers Usually seen in children lt 5 yrs

Cancer risk colon small intestine stomach pancreas breast ovaries uterus testes

lungs kidneys Mutations in STK11 gene

found in 70 of familial cases and 30-70 of sporadic cases

Familial Juvenile PolyposisFamilial Juvenile Polyposis

lt1 of all CRC cases

Autosomal dominant

5 or more juvenile polyps in colon or GI tract

Appear in 1st or 2nd decade

50 lifetime risk of CRC AOO in 30rsquos

Increased risk gastric GI pancreatic CA

~50 of cases have mutations in either the MADH4 or BMPR1A genes

Family Health HistoryFamily Health History

ldquoThe family tree has become the most important genetic test of all The more you know the more tools you have to practice preventive medicinerdquo

Donna Russo Certified Genetic Counselor NY Presbyterian-Columbia Hospital

Goal ClassificationGoal ClassificationAssessment Risk Classification Intervention

Family History

Average

Moderate

(ldquoFamilialrdquo)

HighGenetic

Personalized prevention recommendations

Standard prevention recommendations

Referral for genetic evaluation with personalized prevention recommendations

Consider Genetics Referral forConsider Genetics Referral for

Two or more family members with CRC at least one lt50

Three or more family members wCRC any age

Patient with colon cancer before 40 yrs

Endometrial cancer and family history of CRC lt50

Persons with more than one primary CRC lt50 yrs or with both endometrial CA and CRC

Family or personal history of CRC and one or more 1st degree relative with an HNPCC-related cancer one diagnosed lt50 yrs

Same side of family

Consider Genetics Referral forConsider Genetics Referral for

MSI andor IHC tumor results suspicious for HNPCC

Autosomal dominant pattern of cancers in the family

Persons with 15 or more adenomatous colorectal polyps

Persons with multiple hamartomatous or juvenile GI polyps

Persons with a family history of a known hereditary cancer syndrome

CRC Risk ManagementCRC Risk Management

Average Risk

1 No family history CRC OR2 One 2nd or 3rd degree relative with CRC

FOBT annually + flex sig every 5 years OR Colonoscopy every 10 years OR DCBE every 5 years

Age to Begin50 years

CRC Risk ManagementCRC Risk ManagementModerateFamily history Two 1st degree relatives with CRC any age

or one 1st degree relative with CRC lt 60- Colonoscopy every 5 yrs

One 1st degree relative with CRC gt60 or two 2nd degree relatives with CRC any age- Average risk screening

Or 5-10 yrs earlier than earliest case in family

Age to begin

40 years

40 years

CRC Risk ManagementCRC Risk Management

Age to Begin

HNPCC or suspected HNPCC 20-25 years 1 Colonoscopy every 1-2 yrs

2 Genetic counseling consider genetic testing

FAP or suspected FAP 10-12 years 1 Flex sig or colonoscopy every1-2 yrs

2 Genetic counseling consider genetic testing

Case 1 JoanCase 1 Joan Joan age 38 was recently diagnosed with

endometrial cancer Family history reveals

1 Paternal grandmother endometrial cancer age 50 2 Paternal uncle colon cancer age 48 3 Father colonoscopy at age 50 four adenomatous

polyps removed 4 No other significant history 5 Both sides of the family are Northern European

Caucasian

Pedigree Case 1Pedigree Case 1French Irish Scottish German English

88 yr

61 yr 63 yr

4 polyps

50 yrs 38 yr

35 yrDx 38

8 yr10 yr

CRC Dx 48

Dx 50

KEYKEY

Endometrial CA

Colorectal CA

Adenomatous Polyps

Case 1 AssessmentCase 1 Assessment Joan meets Amsterdam II Criteria and is at risk for HNPCC

Refer to genetics for cancer genetic counseling and discussion of genetic testing for HNPCC

Testing options

1 Direct gene testing of MLH1 and MSH2 OR

2 MSIIHC screening of tumor tissue with gene sequencing if MSI positive

Case 2 TedCase 2 Ted Ted is 30 and wants a colonoscopy because his mother

was just diagnosed with colon cancer after routine screening at age 54 Family history reveals

1 Paternal grandfather died of CRC at age 79

2 No hx of endometrial ovarian small bowel or ureterkidney cancer on either side of family

3 Two maternal aunts cervical cancer at ages 30 amp 34

4 Maternal grandmother breast cancer age 85

Pedigree Case 2Pedigree Case 2Italian Irish German

KEY

CRC

Breast CA

Cervical CA

84

d 58 MIBrCa 85 yrs

d87

55 58 60

Colon CA 54 yrs

Cervical CA 30 yrs

Cervical CA 32 yrs

34 yrs 30 yrs

CRC 79 d82

56

Case 2 TedCase 2 Ted Verify Diagnoses Obtain and review pathology reports on

all reported cancers whenever possible

If diagnoses are correct Ted has no family history indicative of a known colon cancer syndrome (HNPCC FAP other)

Tedrsquos lifetime risk of colorectal CA is increased 2 to 3 fold due to one affected first degree relative (gt50)

Moderatefamilial risk Screening by colonoscopy starting at age 40 or 10 yrs earlier than earliest case in family is reasonable

Chemo PreventionChemo Prevention Evidence that ASA NSAIDs Calcium and COX-2

inhibitors may reduce incidence of CA by reducing ofadenomas

1048707 40-50 risk reduction for developing colorectal CA regardless of location in colon age gender and race

Generally performed by RCTrsquos in patients with priorcolorectal CA followed for recurrence of adenomas

Diet fiber and antioxidant vitamins have not beenshown by RCTrsquos to decrease risk of recurrent adenomas

COX-2irsquos and Sulindac have been shown to reduce thenumber of adenomas found in FAP alone

1048707 Not effective for sporadic colon CA 1048707 Actually can cause regression of adenomas

Prevalence of Adenomas and Prevalence of Adenomas and Incidence of Colon CancerIncidence of Colon Cancer

Age gt50 years with any adenomas 25-40

Lifetime risk of cancer at age 50 years 5 for females 6 for males

Persons with advanced adenomas are at greatest risk

Risk Factors for Colorectal Cancer Risk Factors for Colorectal Cancer (CRC)(CRC)

Aging Personal history of CRC or adenomas High-fat low-fiber diet Inflammatory bowel disease Family history of CRC Hereditary colon cancer syndromes

Risk of Colorectal Cancer Risk of Colorectal Cancer (CRC)(CRC)

0 20 40 60 80 100

Personal History of Colorectal Neoplasia

General Population

Inflammatory Bowel Disease

Familial Adenomatous Polyposis

(FAP)

HNPCC Mutation

Lifetime Risk ()

5

15-20

15-40

70-80

gt95

Colorectal CancerColorectal CancerStatistics in the USStatistics in the US

Second overall leading cause of cancer-related deaths in the US

Estimated 149000 new cases and 50000 deaths in the year 2008

Declining trends between 1990 and 1996 Incidence rate ~21 per year Mortality rates ~17 per year

Family History Empiric RisksFamily History Empiric RisksLifetime Risk CRC

General population in US ~2 to 6

One 1st degree relative with CRC 2-3 fold

Two 1st degree relatives with CRC 3-4 fold

1st degree relative with CRC lt50 3-4 fold

One 2nd or 3rd degree relative with CRC

~15 fold

Two 2nd degree relatives with CRC 2-3 fold

OutlineOutline Hereditary colorectal cancer syndromes Cancer family history ndash a primary tool Evaluating your patients for familial CRC risk Genetic counseling and testing for hereditary

colorectal cancer How when where to refer patients for genetic

services

Colorectal CancerColorectal Cancer

~5-8 of all cases of CRC are hereditary

~15-20 are ldquofamilialrdquomultifactorial

~75 of cases are sporadic

Characteristics of Average RiskCharacteristics of Average Risk

No well-defined threshold between sporadic and familial CRC at this time

Probably safe to include individuals with No personal risk factors or family history of CRC One 2nd or 3rd degree relative with CRC gt60 years with no

other family history of CRC

Characteristics of ldquoFamilialrdquo CRCCharacteristics of ldquoFamilialrdquo CRC

ldquoClusteringrdquo of colon cancer cases in the family (gt50 at diagnosis) without clear dominant pattern or

One close relative with CRC lt60 years and family history does not meet criteria for known hereditary CRC syndromes

Likely to be multiple low penetrant genes plus environmental factors at play

Family members warrant earlier CRC screening Starting at 40 years or 5-10 years earlier than age of diagnosis

of the youngest affected relative

Characteristics of Hereditary Characteristics of Hereditary CRCCRC

Multiple relatives with colorectal cancer One or more diagnosed at an early age (lt50)

Sequential generations affected Except in autosomal recessive syndromes

Other cancers in the family known to be associated with CRC (uterine ovarian GI)

Multiple primary tumors or polyps

Hereditary CRC SyndromesHereditary CRC Syndromes Hereditary Non-Polyposis Colorectal Cancer (HNPCC)

Variants Muir-Torre Turcot Familial Adenomatous Polyposis (FAP)

Variants Gardner Turcot Attenuated FAP APC mutation in Ashkenazi Jews

Others Multiple adenomatous polyposis syndromeMYH gene (MAP) Peutz-Jeghers syndrome (PJS) Familial Juvenile Polyposis (FJP)

HNPCC AKA ldquoLynch SyndromerdquoHNPCC AKA ldquoLynch Syndromerdquo

2-3 of all colorectal cancer cases Autosomal dominant high penetrance Typical age of CA onset is 40-50 years Multiple affected generations 60-70 right-sidedproximal CRC tumors Polyps may be present multiple primaries

common Can overlap with AFAP

HNPCCHNPCCbull Lifetime cancer risks

ndash Colorectal 80

ndash Endometrial 20-60

ndash Gastric 13-19

ndash Ovarian 9-12

ndash Biliary Tract 2

ndash Urinary Tract 4

ndash Small Bowel 1-4

ndash BrainCNS 1-3

HNPCCHNPCCClinical Diagnostic CriteriaClinical Diagnostic Criteria

Amsterdam II Criteria (3-2-1) 3 or more relatives with an HNPCC-related cancer

one of whom is a 1st degree relative of the other two 2 or more successive generations affected

1 or more cancers diagnosed before age 50

HNPCCHNPCC Caused by mutations or deletions in mismatched

repair (MMR) genes MSH2 MLH1 MSH6 (PMS2)

50 of families meeting Amsterdam II Criteria have detectable mutations

TestingScreening options Direct genetic testing of MMR genes (in select families) Initial screening of the tumor tissue by MSIIHC

MSIIHC ScreeningMSIIHC Screening Microsatellite Instability (MSI) on tumor tissue

can be used to screen for HNPCC in select cases

Immunohistochemistry (IHC) on tumor tissue

can be used to detect the presence or absence of the mismatch repair proteins (MSH2 MLH1 etc)

ldquoScreen positiverdquo individuals can be offered cancer genetic counselingassessment and targeted genetic testing

FAPFAP 1 in 10000 incidence 100rsquos to 1000rsquos of colonic adenomas by teens

Cancer risk colon gastric duodenum (periampulla) small bowel pancreas papillary thyroid childhood hepatoblastoma

7 risk of CRC by 21 yrs 93 by 50 yrs Autosomal dominant APC gene mutations Variants Gardner Turcot

FAP - SurveillanceFAP - Surveillance Colon

Annual sigmoidoscopy age 10-12 yrs Prophylactic colectomy following polyp detection with

continued surveillance of rectum ileal pouch Duodenalgastric

EGD age 25 repeat 1-3 yrs Thyroid

Annual PE age 10 Hepatoblastoma

Annual screen by abd US amp AFP from birth to 5 yrs

Attenuated FAPAttenuated FAP 20 to 100 polyps usually more proximal

Onset later than FAP average AOO = 50 Lifetime risk of CRC = 80

Extracolonic tumors occur at same rate as FAP Variant of FAP mutations in same APC gene Surveillance

annual colonoscopy starting late teens or early 20rsquos Option of subtotal colectomy

Genetic Testing FAPAFAPGenetic Testing FAPAFAP Test an affected family member first

After genetic counseling and informed consent

APC gene testing can confirm a suspected diagnosis

Family members of a person with a known APC mutation can have mutation-specific testing

Genetic testing for children at risk for FAP can be considered before beginning colon screening

APC gene mutation inAPC gene mutation inAshkenazi JewsAshkenazi Jews

Missense mutation (I1307K) associated with increased risk of CRC and adenomas in Ashkenazi Jews (AJ)

Found in 6 of the general AJ population

12 of AJs with CRC

29 of AJs with CRC and a positive family history

Lifetime risk of CRC in mutation carrier is 10-20

Screening colonoscopy every 2-5 yrs starting at 35 yrs

MAP syndromeMYH geneMAP syndromeMYH gene Multiple adenomatous polyposis (MAP) syndrome

Autosomal recessive mutations in the MYH gene Median number of polyps = 55 Mean age of polyp diagnosis = 30-50 years Polyps mainly small mildly dysplastic tubular adenomas Some

tubulovillous hyperplastic serrated adenomas microadenomas

30 of individuals with 15-100 polyps have homozygous mutations in the MYH gene

Genetic testing should be offered if gt15 polyps (and APC gene testing negative)

Peutz-Jeghers SyndromePeutz-Jeghers Syndrome lt1 of all CRC cases Hamartomatous polyps of GI tract as early as 1st decade Mucocutaneous hyper pigmentation

lips mouth buccal mucosa fingers Usually seen in children lt 5 yrs

Cancer risk colon small intestine stomach pancreas breast ovaries uterus testes

lungs kidneys Mutations in STK11 gene

found in 70 of familial cases and 30-70 of sporadic cases

Familial Juvenile PolyposisFamilial Juvenile Polyposis

lt1 of all CRC cases

Autosomal dominant

5 or more juvenile polyps in colon or GI tract

Appear in 1st or 2nd decade

50 lifetime risk of CRC AOO in 30rsquos

Increased risk gastric GI pancreatic CA

~50 of cases have mutations in either the MADH4 or BMPR1A genes

Family Health HistoryFamily Health History

ldquoThe family tree has become the most important genetic test of all The more you know the more tools you have to practice preventive medicinerdquo

Donna Russo Certified Genetic Counselor NY Presbyterian-Columbia Hospital

Goal ClassificationGoal ClassificationAssessment Risk Classification Intervention

Family History

Average

Moderate

(ldquoFamilialrdquo)

HighGenetic

Personalized prevention recommendations

Standard prevention recommendations

Referral for genetic evaluation with personalized prevention recommendations

Consider Genetics Referral forConsider Genetics Referral for

Two or more family members with CRC at least one lt50

Three or more family members wCRC any age

Patient with colon cancer before 40 yrs

Endometrial cancer and family history of CRC lt50

Persons with more than one primary CRC lt50 yrs or with both endometrial CA and CRC

Family or personal history of CRC and one or more 1st degree relative with an HNPCC-related cancer one diagnosed lt50 yrs

Same side of family

Consider Genetics Referral forConsider Genetics Referral for

MSI andor IHC tumor results suspicious for HNPCC

Autosomal dominant pattern of cancers in the family

Persons with 15 or more adenomatous colorectal polyps

Persons with multiple hamartomatous or juvenile GI polyps

Persons with a family history of a known hereditary cancer syndrome

CRC Risk ManagementCRC Risk Management

Average Risk

1 No family history CRC OR2 One 2nd or 3rd degree relative with CRC

FOBT annually + flex sig every 5 years OR Colonoscopy every 10 years OR DCBE every 5 years

Age to Begin50 years

CRC Risk ManagementCRC Risk ManagementModerateFamily history Two 1st degree relatives with CRC any age

or one 1st degree relative with CRC lt 60- Colonoscopy every 5 yrs

One 1st degree relative with CRC gt60 or two 2nd degree relatives with CRC any age- Average risk screening

Or 5-10 yrs earlier than earliest case in family

Age to begin

40 years

40 years

CRC Risk ManagementCRC Risk Management

Age to Begin

HNPCC or suspected HNPCC 20-25 years 1 Colonoscopy every 1-2 yrs

2 Genetic counseling consider genetic testing

FAP or suspected FAP 10-12 years 1 Flex sig or colonoscopy every1-2 yrs

2 Genetic counseling consider genetic testing

Case 1 JoanCase 1 Joan Joan age 38 was recently diagnosed with

endometrial cancer Family history reveals

1 Paternal grandmother endometrial cancer age 50 2 Paternal uncle colon cancer age 48 3 Father colonoscopy at age 50 four adenomatous

polyps removed 4 No other significant history 5 Both sides of the family are Northern European

Caucasian

Pedigree Case 1Pedigree Case 1French Irish Scottish German English

88 yr

61 yr 63 yr

4 polyps

50 yrs 38 yr

35 yrDx 38

8 yr10 yr

CRC Dx 48

Dx 50

KEYKEY

Endometrial CA

Colorectal CA

Adenomatous Polyps

Case 1 AssessmentCase 1 Assessment Joan meets Amsterdam II Criteria and is at risk for HNPCC

Refer to genetics for cancer genetic counseling and discussion of genetic testing for HNPCC

Testing options

1 Direct gene testing of MLH1 and MSH2 OR

2 MSIIHC screening of tumor tissue with gene sequencing if MSI positive

Case 2 TedCase 2 Ted Ted is 30 and wants a colonoscopy because his mother

was just diagnosed with colon cancer after routine screening at age 54 Family history reveals

1 Paternal grandfather died of CRC at age 79

2 No hx of endometrial ovarian small bowel or ureterkidney cancer on either side of family

3 Two maternal aunts cervical cancer at ages 30 amp 34

4 Maternal grandmother breast cancer age 85

Pedigree Case 2Pedigree Case 2Italian Irish German

KEY

CRC

Breast CA

Cervical CA

84

d 58 MIBrCa 85 yrs

d87

55 58 60

Colon CA 54 yrs

Cervical CA 30 yrs

Cervical CA 32 yrs

34 yrs 30 yrs

CRC 79 d82

56

Case 2 TedCase 2 Ted Verify Diagnoses Obtain and review pathology reports on

all reported cancers whenever possible

If diagnoses are correct Ted has no family history indicative of a known colon cancer syndrome (HNPCC FAP other)

Tedrsquos lifetime risk of colorectal CA is increased 2 to 3 fold due to one affected first degree relative (gt50)

Moderatefamilial risk Screening by colonoscopy starting at age 40 or 10 yrs earlier than earliest case in family is reasonable

Chemo PreventionChemo Prevention Evidence that ASA NSAIDs Calcium and COX-2

inhibitors may reduce incidence of CA by reducing ofadenomas

1048707 40-50 risk reduction for developing colorectal CA regardless of location in colon age gender and race

Generally performed by RCTrsquos in patients with priorcolorectal CA followed for recurrence of adenomas

Diet fiber and antioxidant vitamins have not beenshown by RCTrsquos to decrease risk of recurrent adenomas

COX-2irsquos and Sulindac have been shown to reduce thenumber of adenomas found in FAP alone

1048707 Not effective for sporadic colon CA 1048707 Actually can cause regression of adenomas

Risk Factors for Colorectal Cancer Risk Factors for Colorectal Cancer (CRC)(CRC)

Aging Personal history of CRC or adenomas High-fat low-fiber diet Inflammatory bowel disease Family history of CRC Hereditary colon cancer syndromes

Risk of Colorectal Cancer Risk of Colorectal Cancer (CRC)(CRC)

0 20 40 60 80 100

Personal History of Colorectal Neoplasia

General Population

Inflammatory Bowel Disease

Familial Adenomatous Polyposis

(FAP)

HNPCC Mutation

Lifetime Risk ()

5

15-20

15-40

70-80

gt95

Colorectal CancerColorectal CancerStatistics in the USStatistics in the US

Second overall leading cause of cancer-related deaths in the US

Estimated 149000 new cases and 50000 deaths in the year 2008

Declining trends between 1990 and 1996 Incidence rate ~21 per year Mortality rates ~17 per year

Family History Empiric RisksFamily History Empiric RisksLifetime Risk CRC

General population in US ~2 to 6

One 1st degree relative with CRC 2-3 fold

Two 1st degree relatives with CRC 3-4 fold

1st degree relative with CRC lt50 3-4 fold

One 2nd or 3rd degree relative with CRC

~15 fold

Two 2nd degree relatives with CRC 2-3 fold

OutlineOutline Hereditary colorectal cancer syndromes Cancer family history ndash a primary tool Evaluating your patients for familial CRC risk Genetic counseling and testing for hereditary

colorectal cancer How when where to refer patients for genetic

services

Colorectal CancerColorectal Cancer

~5-8 of all cases of CRC are hereditary

~15-20 are ldquofamilialrdquomultifactorial

~75 of cases are sporadic

Characteristics of Average RiskCharacteristics of Average Risk

No well-defined threshold between sporadic and familial CRC at this time

Probably safe to include individuals with No personal risk factors or family history of CRC One 2nd or 3rd degree relative with CRC gt60 years with no

other family history of CRC

Characteristics of ldquoFamilialrdquo CRCCharacteristics of ldquoFamilialrdquo CRC

ldquoClusteringrdquo of colon cancer cases in the family (gt50 at diagnosis) without clear dominant pattern or

One close relative with CRC lt60 years and family history does not meet criteria for known hereditary CRC syndromes

Likely to be multiple low penetrant genes plus environmental factors at play

Family members warrant earlier CRC screening Starting at 40 years or 5-10 years earlier than age of diagnosis

of the youngest affected relative

Characteristics of Hereditary Characteristics of Hereditary CRCCRC

Multiple relatives with colorectal cancer One or more diagnosed at an early age (lt50)

Sequential generations affected Except in autosomal recessive syndromes

Other cancers in the family known to be associated with CRC (uterine ovarian GI)

Multiple primary tumors or polyps

Hereditary CRC SyndromesHereditary CRC Syndromes Hereditary Non-Polyposis Colorectal Cancer (HNPCC)

Variants Muir-Torre Turcot Familial Adenomatous Polyposis (FAP)

Variants Gardner Turcot Attenuated FAP APC mutation in Ashkenazi Jews

Others Multiple adenomatous polyposis syndromeMYH gene (MAP) Peutz-Jeghers syndrome (PJS) Familial Juvenile Polyposis (FJP)

HNPCC AKA ldquoLynch SyndromerdquoHNPCC AKA ldquoLynch Syndromerdquo

2-3 of all colorectal cancer cases Autosomal dominant high penetrance Typical age of CA onset is 40-50 years Multiple affected generations 60-70 right-sidedproximal CRC tumors Polyps may be present multiple primaries

common Can overlap with AFAP

HNPCCHNPCCbull Lifetime cancer risks

ndash Colorectal 80

ndash Endometrial 20-60

ndash Gastric 13-19

ndash Ovarian 9-12

ndash Biliary Tract 2

ndash Urinary Tract 4

ndash Small Bowel 1-4

ndash BrainCNS 1-3

HNPCCHNPCCClinical Diagnostic CriteriaClinical Diagnostic Criteria

Amsterdam II Criteria (3-2-1) 3 or more relatives with an HNPCC-related cancer

one of whom is a 1st degree relative of the other two 2 or more successive generations affected

1 or more cancers diagnosed before age 50

HNPCCHNPCC Caused by mutations or deletions in mismatched

repair (MMR) genes MSH2 MLH1 MSH6 (PMS2)

50 of families meeting Amsterdam II Criteria have detectable mutations

TestingScreening options Direct genetic testing of MMR genes (in select families) Initial screening of the tumor tissue by MSIIHC

MSIIHC ScreeningMSIIHC Screening Microsatellite Instability (MSI) on tumor tissue

can be used to screen for HNPCC in select cases

Immunohistochemistry (IHC) on tumor tissue

can be used to detect the presence or absence of the mismatch repair proteins (MSH2 MLH1 etc)

ldquoScreen positiverdquo individuals can be offered cancer genetic counselingassessment and targeted genetic testing

FAPFAP 1 in 10000 incidence 100rsquos to 1000rsquos of colonic adenomas by teens

Cancer risk colon gastric duodenum (periampulla) small bowel pancreas papillary thyroid childhood hepatoblastoma

7 risk of CRC by 21 yrs 93 by 50 yrs Autosomal dominant APC gene mutations Variants Gardner Turcot

FAP - SurveillanceFAP - Surveillance Colon

Annual sigmoidoscopy age 10-12 yrs Prophylactic colectomy following polyp detection with

continued surveillance of rectum ileal pouch Duodenalgastric

EGD age 25 repeat 1-3 yrs Thyroid

Annual PE age 10 Hepatoblastoma

Annual screen by abd US amp AFP from birth to 5 yrs

Attenuated FAPAttenuated FAP 20 to 100 polyps usually more proximal

Onset later than FAP average AOO = 50 Lifetime risk of CRC = 80

Extracolonic tumors occur at same rate as FAP Variant of FAP mutations in same APC gene Surveillance

annual colonoscopy starting late teens or early 20rsquos Option of subtotal colectomy

Genetic Testing FAPAFAPGenetic Testing FAPAFAP Test an affected family member first

After genetic counseling and informed consent

APC gene testing can confirm a suspected diagnosis

Family members of a person with a known APC mutation can have mutation-specific testing

Genetic testing for children at risk for FAP can be considered before beginning colon screening

APC gene mutation inAPC gene mutation inAshkenazi JewsAshkenazi Jews

Missense mutation (I1307K) associated with increased risk of CRC and adenomas in Ashkenazi Jews (AJ)

Found in 6 of the general AJ population

12 of AJs with CRC

29 of AJs with CRC and a positive family history

Lifetime risk of CRC in mutation carrier is 10-20

Screening colonoscopy every 2-5 yrs starting at 35 yrs

MAP syndromeMYH geneMAP syndromeMYH gene Multiple adenomatous polyposis (MAP) syndrome

Autosomal recessive mutations in the MYH gene Median number of polyps = 55 Mean age of polyp diagnosis = 30-50 years Polyps mainly small mildly dysplastic tubular adenomas Some

tubulovillous hyperplastic serrated adenomas microadenomas

30 of individuals with 15-100 polyps have homozygous mutations in the MYH gene

Genetic testing should be offered if gt15 polyps (and APC gene testing negative)

Peutz-Jeghers SyndromePeutz-Jeghers Syndrome lt1 of all CRC cases Hamartomatous polyps of GI tract as early as 1st decade Mucocutaneous hyper pigmentation

lips mouth buccal mucosa fingers Usually seen in children lt 5 yrs

Cancer risk colon small intestine stomach pancreas breast ovaries uterus testes

lungs kidneys Mutations in STK11 gene

found in 70 of familial cases and 30-70 of sporadic cases

Familial Juvenile PolyposisFamilial Juvenile Polyposis

lt1 of all CRC cases

Autosomal dominant

5 or more juvenile polyps in colon or GI tract

Appear in 1st or 2nd decade

50 lifetime risk of CRC AOO in 30rsquos

Increased risk gastric GI pancreatic CA

~50 of cases have mutations in either the MADH4 or BMPR1A genes

Family Health HistoryFamily Health History

ldquoThe family tree has become the most important genetic test of all The more you know the more tools you have to practice preventive medicinerdquo

Donna Russo Certified Genetic Counselor NY Presbyterian-Columbia Hospital

Goal ClassificationGoal ClassificationAssessment Risk Classification Intervention

Family History

Average

Moderate

(ldquoFamilialrdquo)

HighGenetic

Personalized prevention recommendations

Standard prevention recommendations

Referral for genetic evaluation with personalized prevention recommendations

Consider Genetics Referral forConsider Genetics Referral for

Two or more family members with CRC at least one lt50

Three or more family members wCRC any age

Patient with colon cancer before 40 yrs

Endometrial cancer and family history of CRC lt50

Persons with more than one primary CRC lt50 yrs or with both endometrial CA and CRC

Family or personal history of CRC and one or more 1st degree relative with an HNPCC-related cancer one diagnosed lt50 yrs

Same side of family

Consider Genetics Referral forConsider Genetics Referral for

MSI andor IHC tumor results suspicious for HNPCC

Autosomal dominant pattern of cancers in the family

Persons with 15 or more adenomatous colorectal polyps

Persons with multiple hamartomatous or juvenile GI polyps

Persons with a family history of a known hereditary cancer syndrome

CRC Risk ManagementCRC Risk Management

Average Risk

1 No family history CRC OR2 One 2nd or 3rd degree relative with CRC

FOBT annually + flex sig every 5 years OR Colonoscopy every 10 years OR DCBE every 5 years

Age to Begin50 years

CRC Risk ManagementCRC Risk ManagementModerateFamily history Two 1st degree relatives with CRC any age

or one 1st degree relative with CRC lt 60- Colonoscopy every 5 yrs

One 1st degree relative with CRC gt60 or two 2nd degree relatives with CRC any age- Average risk screening

Or 5-10 yrs earlier than earliest case in family

Age to begin

40 years

40 years

CRC Risk ManagementCRC Risk Management

Age to Begin

HNPCC or suspected HNPCC 20-25 years 1 Colonoscopy every 1-2 yrs

2 Genetic counseling consider genetic testing

FAP or suspected FAP 10-12 years 1 Flex sig or colonoscopy every1-2 yrs

2 Genetic counseling consider genetic testing

Case 1 JoanCase 1 Joan Joan age 38 was recently diagnosed with

endometrial cancer Family history reveals

1 Paternal grandmother endometrial cancer age 50 2 Paternal uncle colon cancer age 48 3 Father colonoscopy at age 50 four adenomatous

polyps removed 4 No other significant history 5 Both sides of the family are Northern European

Caucasian

Pedigree Case 1Pedigree Case 1French Irish Scottish German English

88 yr

61 yr 63 yr

4 polyps

50 yrs 38 yr

35 yrDx 38

8 yr10 yr

CRC Dx 48

Dx 50

KEYKEY

Endometrial CA

Colorectal CA

Adenomatous Polyps

Case 1 AssessmentCase 1 Assessment Joan meets Amsterdam II Criteria and is at risk for HNPCC

Refer to genetics for cancer genetic counseling and discussion of genetic testing for HNPCC

Testing options

1 Direct gene testing of MLH1 and MSH2 OR

2 MSIIHC screening of tumor tissue with gene sequencing if MSI positive

Case 2 TedCase 2 Ted Ted is 30 and wants a colonoscopy because his mother

was just diagnosed with colon cancer after routine screening at age 54 Family history reveals

1 Paternal grandfather died of CRC at age 79

2 No hx of endometrial ovarian small bowel or ureterkidney cancer on either side of family

3 Two maternal aunts cervical cancer at ages 30 amp 34

4 Maternal grandmother breast cancer age 85

Pedigree Case 2Pedigree Case 2Italian Irish German

KEY

CRC

Breast CA

Cervical CA

84

d 58 MIBrCa 85 yrs

d87

55 58 60

Colon CA 54 yrs

Cervical CA 30 yrs

Cervical CA 32 yrs

34 yrs 30 yrs

CRC 79 d82

56

Case 2 TedCase 2 Ted Verify Diagnoses Obtain and review pathology reports on

all reported cancers whenever possible

If diagnoses are correct Ted has no family history indicative of a known colon cancer syndrome (HNPCC FAP other)

Tedrsquos lifetime risk of colorectal CA is increased 2 to 3 fold due to one affected first degree relative (gt50)

Moderatefamilial risk Screening by colonoscopy starting at age 40 or 10 yrs earlier than earliest case in family is reasonable

Chemo PreventionChemo Prevention Evidence that ASA NSAIDs Calcium and COX-2

inhibitors may reduce incidence of CA by reducing ofadenomas

1048707 40-50 risk reduction for developing colorectal CA regardless of location in colon age gender and race

Generally performed by RCTrsquos in patients with priorcolorectal CA followed for recurrence of adenomas

Diet fiber and antioxidant vitamins have not beenshown by RCTrsquos to decrease risk of recurrent adenomas

COX-2irsquos and Sulindac have been shown to reduce thenumber of adenomas found in FAP alone

1048707 Not effective for sporadic colon CA 1048707 Actually can cause regression of adenomas

Risk of Colorectal Cancer Risk of Colorectal Cancer (CRC)(CRC)

0 20 40 60 80 100

Personal History of Colorectal Neoplasia

General Population

Inflammatory Bowel Disease

Familial Adenomatous Polyposis

(FAP)

HNPCC Mutation

Lifetime Risk ()

5

15-20

15-40

70-80

gt95

Colorectal CancerColorectal CancerStatistics in the USStatistics in the US

Second overall leading cause of cancer-related deaths in the US

Estimated 149000 new cases and 50000 deaths in the year 2008

Declining trends between 1990 and 1996 Incidence rate ~21 per year Mortality rates ~17 per year

Family History Empiric RisksFamily History Empiric RisksLifetime Risk CRC

General population in US ~2 to 6

One 1st degree relative with CRC 2-3 fold

Two 1st degree relatives with CRC 3-4 fold

1st degree relative with CRC lt50 3-4 fold

One 2nd or 3rd degree relative with CRC

~15 fold

Two 2nd degree relatives with CRC 2-3 fold

OutlineOutline Hereditary colorectal cancer syndromes Cancer family history ndash a primary tool Evaluating your patients for familial CRC risk Genetic counseling and testing for hereditary

colorectal cancer How when where to refer patients for genetic

services

Colorectal CancerColorectal Cancer

~5-8 of all cases of CRC are hereditary

~15-20 are ldquofamilialrdquomultifactorial

~75 of cases are sporadic

Characteristics of Average RiskCharacteristics of Average Risk

No well-defined threshold between sporadic and familial CRC at this time

Probably safe to include individuals with No personal risk factors or family history of CRC One 2nd or 3rd degree relative with CRC gt60 years with no

other family history of CRC

Characteristics of ldquoFamilialrdquo CRCCharacteristics of ldquoFamilialrdquo CRC

ldquoClusteringrdquo of colon cancer cases in the family (gt50 at diagnosis) without clear dominant pattern or

One close relative with CRC lt60 years and family history does not meet criteria for known hereditary CRC syndromes

Likely to be multiple low penetrant genes plus environmental factors at play

Family members warrant earlier CRC screening Starting at 40 years or 5-10 years earlier than age of diagnosis

of the youngest affected relative

Characteristics of Hereditary Characteristics of Hereditary CRCCRC

Multiple relatives with colorectal cancer One or more diagnosed at an early age (lt50)

Sequential generations affected Except in autosomal recessive syndromes

Other cancers in the family known to be associated with CRC (uterine ovarian GI)

Multiple primary tumors or polyps

Hereditary CRC SyndromesHereditary CRC Syndromes Hereditary Non-Polyposis Colorectal Cancer (HNPCC)

Variants Muir-Torre Turcot Familial Adenomatous Polyposis (FAP)

Variants Gardner Turcot Attenuated FAP APC mutation in Ashkenazi Jews

Others Multiple adenomatous polyposis syndromeMYH gene (MAP) Peutz-Jeghers syndrome (PJS) Familial Juvenile Polyposis (FJP)

HNPCC AKA ldquoLynch SyndromerdquoHNPCC AKA ldquoLynch Syndromerdquo

2-3 of all colorectal cancer cases Autosomal dominant high penetrance Typical age of CA onset is 40-50 years Multiple affected generations 60-70 right-sidedproximal CRC tumors Polyps may be present multiple primaries

common Can overlap with AFAP

HNPCCHNPCCbull Lifetime cancer risks

ndash Colorectal 80

ndash Endometrial 20-60

ndash Gastric 13-19

ndash Ovarian 9-12

ndash Biliary Tract 2

ndash Urinary Tract 4

ndash Small Bowel 1-4

ndash BrainCNS 1-3

HNPCCHNPCCClinical Diagnostic CriteriaClinical Diagnostic Criteria

Amsterdam II Criteria (3-2-1) 3 or more relatives with an HNPCC-related cancer

one of whom is a 1st degree relative of the other two 2 or more successive generations affected

1 or more cancers diagnosed before age 50

HNPCCHNPCC Caused by mutations or deletions in mismatched

repair (MMR) genes MSH2 MLH1 MSH6 (PMS2)

50 of families meeting Amsterdam II Criteria have detectable mutations

TestingScreening options Direct genetic testing of MMR genes (in select families) Initial screening of the tumor tissue by MSIIHC

MSIIHC ScreeningMSIIHC Screening Microsatellite Instability (MSI) on tumor tissue

can be used to screen for HNPCC in select cases

Immunohistochemistry (IHC) on tumor tissue

can be used to detect the presence or absence of the mismatch repair proteins (MSH2 MLH1 etc)

ldquoScreen positiverdquo individuals can be offered cancer genetic counselingassessment and targeted genetic testing

FAPFAP 1 in 10000 incidence 100rsquos to 1000rsquos of colonic adenomas by teens

Cancer risk colon gastric duodenum (periampulla) small bowel pancreas papillary thyroid childhood hepatoblastoma

7 risk of CRC by 21 yrs 93 by 50 yrs Autosomal dominant APC gene mutations Variants Gardner Turcot

FAP - SurveillanceFAP - Surveillance Colon

Annual sigmoidoscopy age 10-12 yrs Prophylactic colectomy following polyp detection with

continued surveillance of rectum ileal pouch Duodenalgastric

EGD age 25 repeat 1-3 yrs Thyroid

Annual PE age 10 Hepatoblastoma

Annual screen by abd US amp AFP from birth to 5 yrs

Attenuated FAPAttenuated FAP 20 to 100 polyps usually more proximal

Onset later than FAP average AOO = 50 Lifetime risk of CRC = 80

Extracolonic tumors occur at same rate as FAP Variant of FAP mutations in same APC gene Surveillance

annual colonoscopy starting late teens or early 20rsquos Option of subtotal colectomy

Genetic Testing FAPAFAPGenetic Testing FAPAFAP Test an affected family member first

After genetic counseling and informed consent

APC gene testing can confirm a suspected diagnosis

Family members of a person with a known APC mutation can have mutation-specific testing

Genetic testing for children at risk for FAP can be considered before beginning colon screening

APC gene mutation inAPC gene mutation inAshkenazi JewsAshkenazi Jews

Missense mutation (I1307K) associated with increased risk of CRC and adenomas in Ashkenazi Jews (AJ)

Found in 6 of the general AJ population

12 of AJs with CRC

29 of AJs with CRC and a positive family history

Lifetime risk of CRC in mutation carrier is 10-20

Screening colonoscopy every 2-5 yrs starting at 35 yrs

MAP syndromeMYH geneMAP syndromeMYH gene Multiple adenomatous polyposis (MAP) syndrome

Autosomal recessive mutations in the MYH gene Median number of polyps = 55 Mean age of polyp diagnosis = 30-50 years Polyps mainly small mildly dysplastic tubular adenomas Some

tubulovillous hyperplastic serrated adenomas microadenomas

30 of individuals with 15-100 polyps have homozygous mutations in the MYH gene

Genetic testing should be offered if gt15 polyps (and APC gene testing negative)

Peutz-Jeghers SyndromePeutz-Jeghers Syndrome lt1 of all CRC cases Hamartomatous polyps of GI tract as early as 1st decade Mucocutaneous hyper pigmentation

lips mouth buccal mucosa fingers Usually seen in children lt 5 yrs

Cancer risk colon small intestine stomach pancreas breast ovaries uterus testes

lungs kidneys Mutations in STK11 gene

found in 70 of familial cases and 30-70 of sporadic cases

Familial Juvenile PolyposisFamilial Juvenile Polyposis

lt1 of all CRC cases

Autosomal dominant

5 or more juvenile polyps in colon or GI tract

Appear in 1st or 2nd decade

50 lifetime risk of CRC AOO in 30rsquos

Increased risk gastric GI pancreatic CA

~50 of cases have mutations in either the MADH4 or BMPR1A genes

Family Health HistoryFamily Health History

ldquoThe family tree has become the most important genetic test of all The more you know the more tools you have to practice preventive medicinerdquo

Donna Russo Certified Genetic Counselor NY Presbyterian-Columbia Hospital

Goal ClassificationGoal ClassificationAssessment Risk Classification Intervention

Family History

Average

Moderate

(ldquoFamilialrdquo)

HighGenetic

Personalized prevention recommendations

Standard prevention recommendations

Referral for genetic evaluation with personalized prevention recommendations

Consider Genetics Referral forConsider Genetics Referral for

Two or more family members with CRC at least one lt50

Three or more family members wCRC any age

Patient with colon cancer before 40 yrs

Endometrial cancer and family history of CRC lt50

Persons with more than one primary CRC lt50 yrs or with both endometrial CA and CRC

Family or personal history of CRC and one or more 1st degree relative with an HNPCC-related cancer one diagnosed lt50 yrs

Same side of family

Consider Genetics Referral forConsider Genetics Referral for

MSI andor IHC tumor results suspicious for HNPCC

Autosomal dominant pattern of cancers in the family

Persons with 15 or more adenomatous colorectal polyps

Persons with multiple hamartomatous or juvenile GI polyps

Persons with a family history of a known hereditary cancer syndrome

CRC Risk ManagementCRC Risk Management

Average Risk

1 No family history CRC OR2 One 2nd or 3rd degree relative with CRC

FOBT annually + flex sig every 5 years OR Colonoscopy every 10 years OR DCBE every 5 years

Age to Begin50 years

CRC Risk ManagementCRC Risk ManagementModerateFamily history Two 1st degree relatives with CRC any age

or one 1st degree relative with CRC lt 60- Colonoscopy every 5 yrs

One 1st degree relative with CRC gt60 or two 2nd degree relatives with CRC any age- Average risk screening

Or 5-10 yrs earlier than earliest case in family

Age to begin

40 years

40 years

CRC Risk ManagementCRC Risk Management

Age to Begin

HNPCC or suspected HNPCC 20-25 years 1 Colonoscopy every 1-2 yrs

2 Genetic counseling consider genetic testing

FAP or suspected FAP 10-12 years 1 Flex sig or colonoscopy every1-2 yrs

2 Genetic counseling consider genetic testing

Case 1 JoanCase 1 Joan Joan age 38 was recently diagnosed with

endometrial cancer Family history reveals

1 Paternal grandmother endometrial cancer age 50 2 Paternal uncle colon cancer age 48 3 Father colonoscopy at age 50 four adenomatous

polyps removed 4 No other significant history 5 Both sides of the family are Northern European

Caucasian

Pedigree Case 1Pedigree Case 1French Irish Scottish German English

88 yr

61 yr 63 yr

4 polyps

50 yrs 38 yr

35 yrDx 38

8 yr10 yr

CRC Dx 48

Dx 50

KEYKEY

Endometrial CA

Colorectal CA

Adenomatous Polyps

Case 1 AssessmentCase 1 Assessment Joan meets Amsterdam II Criteria and is at risk for HNPCC

Refer to genetics for cancer genetic counseling and discussion of genetic testing for HNPCC

Testing options

1 Direct gene testing of MLH1 and MSH2 OR

2 MSIIHC screening of tumor tissue with gene sequencing if MSI positive

Case 2 TedCase 2 Ted Ted is 30 and wants a colonoscopy because his mother

was just diagnosed with colon cancer after routine screening at age 54 Family history reveals

1 Paternal grandfather died of CRC at age 79

2 No hx of endometrial ovarian small bowel or ureterkidney cancer on either side of family

3 Two maternal aunts cervical cancer at ages 30 amp 34

4 Maternal grandmother breast cancer age 85

Pedigree Case 2Pedigree Case 2Italian Irish German

KEY

CRC

Breast CA

Cervical CA

84

d 58 MIBrCa 85 yrs

d87

55 58 60

Colon CA 54 yrs

Cervical CA 30 yrs

Cervical CA 32 yrs

34 yrs 30 yrs

CRC 79 d82

56

Case 2 TedCase 2 Ted Verify Diagnoses Obtain and review pathology reports on

all reported cancers whenever possible

If diagnoses are correct Ted has no family history indicative of a known colon cancer syndrome (HNPCC FAP other)

Tedrsquos lifetime risk of colorectal CA is increased 2 to 3 fold due to one affected first degree relative (gt50)

Moderatefamilial risk Screening by colonoscopy starting at age 40 or 10 yrs earlier than earliest case in family is reasonable

Chemo PreventionChemo Prevention Evidence that ASA NSAIDs Calcium and COX-2

inhibitors may reduce incidence of CA by reducing ofadenomas

1048707 40-50 risk reduction for developing colorectal CA regardless of location in colon age gender and race

Generally performed by RCTrsquos in patients with priorcolorectal CA followed for recurrence of adenomas

Diet fiber and antioxidant vitamins have not beenshown by RCTrsquos to decrease risk of recurrent adenomas

COX-2irsquos and Sulindac have been shown to reduce thenumber of adenomas found in FAP alone

1048707 Not effective for sporadic colon CA 1048707 Actually can cause regression of adenomas

Colorectal CancerColorectal CancerStatistics in the USStatistics in the US

Second overall leading cause of cancer-related deaths in the US

Estimated 149000 new cases and 50000 deaths in the year 2008

Declining trends between 1990 and 1996 Incidence rate ~21 per year Mortality rates ~17 per year

Family History Empiric RisksFamily History Empiric RisksLifetime Risk CRC

General population in US ~2 to 6

One 1st degree relative with CRC 2-3 fold

Two 1st degree relatives with CRC 3-4 fold

1st degree relative with CRC lt50 3-4 fold

One 2nd or 3rd degree relative with CRC

~15 fold

Two 2nd degree relatives with CRC 2-3 fold

OutlineOutline Hereditary colorectal cancer syndromes Cancer family history ndash a primary tool Evaluating your patients for familial CRC risk Genetic counseling and testing for hereditary

colorectal cancer How when where to refer patients for genetic

services

Colorectal CancerColorectal Cancer

~5-8 of all cases of CRC are hereditary

~15-20 are ldquofamilialrdquomultifactorial

~75 of cases are sporadic

Characteristics of Average RiskCharacteristics of Average Risk

No well-defined threshold between sporadic and familial CRC at this time

Probably safe to include individuals with No personal risk factors or family history of CRC One 2nd or 3rd degree relative with CRC gt60 years with no

other family history of CRC

Characteristics of ldquoFamilialrdquo CRCCharacteristics of ldquoFamilialrdquo CRC

ldquoClusteringrdquo of colon cancer cases in the family (gt50 at diagnosis) without clear dominant pattern or

One close relative with CRC lt60 years and family history does not meet criteria for known hereditary CRC syndromes

Likely to be multiple low penetrant genes plus environmental factors at play

Family members warrant earlier CRC screening Starting at 40 years or 5-10 years earlier than age of diagnosis

of the youngest affected relative

Characteristics of Hereditary Characteristics of Hereditary CRCCRC

Multiple relatives with colorectal cancer One or more diagnosed at an early age (lt50)

Sequential generations affected Except in autosomal recessive syndromes

Other cancers in the family known to be associated with CRC (uterine ovarian GI)

Multiple primary tumors or polyps

Hereditary CRC SyndromesHereditary CRC Syndromes Hereditary Non-Polyposis Colorectal Cancer (HNPCC)

Variants Muir-Torre Turcot Familial Adenomatous Polyposis (FAP)

Variants Gardner Turcot Attenuated FAP APC mutation in Ashkenazi Jews

Others Multiple adenomatous polyposis syndromeMYH gene (MAP) Peutz-Jeghers syndrome (PJS) Familial Juvenile Polyposis (FJP)

HNPCC AKA ldquoLynch SyndromerdquoHNPCC AKA ldquoLynch Syndromerdquo

2-3 of all colorectal cancer cases Autosomal dominant high penetrance Typical age of CA onset is 40-50 years Multiple affected generations 60-70 right-sidedproximal CRC tumors Polyps may be present multiple primaries

common Can overlap with AFAP

HNPCCHNPCCbull Lifetime cancer risks

ndash Colorectal 80

ndash Endometrial 20-60

ndash Gastric 13-19

ndash Ovarian 9-12

ndash Biliary Tract 2

ndash Urinary Tract 4

ndash Small Bowel 1-4

ndash BrainCNS 1-3

HNPCCHNPCCClinical Diagnostic CriteriaClinical Diagnostic Criteria

Amsterdam II Criteria (3-2-1) 3 or more relatives with an HNPCC-related cancer

one of whom is a 1st degree relative of the other two 2 or more successive generations affected

1 or more cancers diagnosed before age 50

HNPCCHNPCC Caused by mutations or deletions in mismatched

repair (MMR) genes MSH2 MLH1 MSH6 (PMS2)

50 of families meeting Amsterdam II Criteria have detectable mutations

TestingScreening options Direct genetic testing of MMR genes (in select families) Initial screening of the tumor tissue by MSIIHC

MSIIHC ScreeningMSIIHC Screening Microsatellite Instability (MSI) on tumor tissue

can be used to screen for HNPCC in select cases

Immunohistochemistry (IHC) on tumor tissue

can be used to detect the presence or absence of the mismatch repair proteins (MSH2 MLH1 etc)

ldquoScreen positiverdquo individuals can be offered cancer genetic counselingassessment and targeted genetic testing

FAPFAP 1 in 10000 incidence 100rsquos to 1000rsquos of colonic adenomas by teens

Cancer risk colon gastric duodenum (periampulla) small bowel pancreas papillary thyroid childhood hepatoblastoma

7 risk of CRC by 21 yrs 93 by 50 yrs Autosomal dominant APC gene mutations Variants Gardner Turcot

FAP - SurveillanceFAP - Surveillance Colon

Annual sigmoidoscopy age 10-12 yrs Prophylactic colectomy following polyp detection with

continued surveillance of rectum ileal pouch Duodenalgastric

EGD age 25 repeat 1-3 yrs Thyroid

Annual PE age 10 Hepatoblastoma

Annual screen by abd US amp AFP from birth to 5 yrs

Attenuated FAPAttenuated FAP 20 to 100 polyps usually more proximal

Onset later than FAP average AOO = 50 Lifetime risk of CRC = 80

Extracolonic tumors occur at same rate as FAP Variant of FAP mutations in same APC gene Surveillance

annual colonoscopy starting late teens or early 20rsquos Option of subtotal colectomy

Genetic Testing FAPAFAPGenetic Testing FAPAFAP Test an affected family member first

After genetic counseling and informed consent

APC gene testing can confirm a suspected diagnosis

Family members of a person with a known APC mutation can have mutation-specific testing

Genetic testing for children at risk for FAP can be considered before beginning colon screening

APC gene mutation inAPC gene mutation inAshkenazi JewsAshkenazi Jews

Missense mutation (I1307K) associated with increased risk of CRC and adenomas in Ashkenazi Jews (AJ)

Found in 6 of the general AJ population

12 of AJs with CRC

29 of AJs with CRC and a positive family history

Lifetime risk of CRC in mutation carrier is 10-20

Screening colonoscopy every 2-5 yrs starting at 35 yrs

MAP syndromeMYH geneMAP syndromeMYH gene Multiple adenomatous polyposis (MAP) syndrome

Autosomal recessive mutations in the MYH gene Median number of polyps = 55 Mean age of polyp diagnosis = 30-50 years Polyps mainly small mildly dysplastic tubular adenomas Some

tubulovillous hyperplastic serrated adenomas microadenomas

30 of individuals with 15-100 polyps have homozygous mutations in the MYH gene

Genetic testing should be offered if gt15 polyps (and APC gene testing negative)

Peutz-Jeghers SyndromePeutz-Jeghers Syndrome lt1 of all CRC cases Hamartomatous polyps of GI tract as early as 1st decade Mucocutaneous hyper pigmentation

lips mouth buccal mucosa fingers Usually seen in children lt 5 yrs

Cancer risk colon small intestine stomach pancreas breast ovaries uterus testes

lungs kidneys Mutations in STK11 gene

found in 70 of familial cases and 30-70 of sporadic cases

Familial Juvenile PolyposisFamilial Juvenile Polyposis

lt1 of all CRC cases

Autosomal dominant

5 or more juvenile polyps in colon or GI tract

Appear in 1st or 2nd decade

50 lifetime risk of CRC AOO in 30rsquos

Increased risk gastric GI pancreatic CA

~50 of cases have mutations in either the MADH4 or BMPR1A genes

Family Health HistoryFamily Health History

ldquoThe family tree has become the most important genetic test of all The more you know the more tools you have to practice preventive medicinerdquo

Donna Russo Certified Genetic Counselor NY Presbyterian-Columbia Hospital

Goal ClassificationGoal ClassificationAssessment Risk Classification Intervention

Family History

Average

Moderate

(ldquoFamilialrdquo)

HighGenetic

Personalized prevention recommendations

Standard prevention recommendations

Referral for genetic evaluation with personalized prevention recommendations

Consider Genetics Referral forConsider Genetics Referral for

Two or more family members with CRC at least one lt50

Three or more family members wCRC any age

Patient with colon cancer before 40 yrs

Endometrial cancer and family history of CRC lt50

Persons with more than one primary CRC lt50 yrs or with both endometrial CA and CRC

Family or personal history of CRC and one or more 1st degree relative with an HNPCC-related cancer one diagnosed lt50 yrs

Same side of family

Consider Genetics Referral forConsider Genetics Referral for

MSI andor IHC tumor results suspicious for HNPCC

Autosomal dominant pattern of cancers in the family

Persons with 15 or more adenomatous colorectal polyps

Persons with multiple hamartomatous or juvenile GI polyps

Persons with a family history of a known hereditary cancer syndrome

CRC Risk ManagementCRC Risk Management

Average Risk

1 No family history CRC OR2 One 2nd or 3rd degree relative with CRC

FOBT annually + flex sig every 5 years OR Colonoscopy every 10 years OR DCBE every 5 years

Age to Begin50 years

CRC Risk ManagementCRC Risk ManagementModerateFamily history Two 1st degree relatives with CRC any age

or one 1st degree relative with CRC lt 60- Colonoscopy every 5 yrs

One 1st degree relative with CRC gt60 or two 2nd degree relatives with CRC any age- Average risk screening

Or 5-10 yrs earlier than earliest case in family

Age to begin

40 years

40 years

CRC Risk ManagementCRC Risk Management

Age to Begin

HNPCC or suspected HNPCC 20-25 years 1 Colonoscopy every 1-2 yrs

2 Genetic counseling consider genetic testing

FAP or suspected FAP 10-12 years 1 Flex sig or colonoscopy every1-2 yrs

2 Genetic counseling consider genetic testing

Case 1 JoanCase 1 Joan Joan age 38 was recently diagnosed with

endometrial cancer Family history reveals

1 Paternal grandmother endometrial cancer age 50 2 Paternal uncle colon cancer age 48 3 Father colonoscopy at age 50 four adenomatous

polyps removed 4 No other significant history 5 Both sides of the family are Northern European

Caucasian

Pedigree Case 1Pedigree Case 1French Irish Scottish German English

88 yr

61 yr 63 yr

4 polyps

50 yrs 38 yr

35 yrDx 38

8 yr10 yr

CRC Dx 48

Dx 50

KEYKEY

Endometrial CA

Colorectal CA

Adenomatous Polyps

Case 1 AssessmentCase 1 Assessment Joan meets Amsterdam II Criteria and is at risk for HNPCC

Refer to genetics for cancer genetic counseling and discussion of genetic testing for HNPCC

Testing options

1 Direct gene testing of MLH1 and MSH2 OR

2 MSIIHC screening of tumor tissue with gene sequencing if MSI positive

Case 2 TedCase 2 Ted Ted is 30 and wants a colonoscopy because his mother

was just diagnosed with colon cancer after routine screening at age 54 Family history reveals

1 Paternal grandfather died of CRC at age 79

2 No hx of endometrial ovarian small bowel or ureterkidney cancer on either side of family

3 Two maternal aunts cervical cancer at ages 30 amp 34

4 Maternal grandmother breast cancer age 85

Pedigree Case 2Pedigree Case 2Italian Irish German

KEY

CRC

Breast CA

Cervical CA

84

d 58 MIBrCa 85 yrs

d87

55 58 60

Colon CA 54 yrs

Cervical CA 30 yrs

Cervical CA 32 yrs

34 yrs 30 yrs

CRC 79 d82

56

Case 2 TedCase 2 Ted Verify Diagnoses Obtain and review pathology reports on

all reported cancers whenever possible

If diagnoses are correct Ted has no family history indicative of a known colon cancer syndrome (HNPCC FAP other)

Tedrsquos lifetime risk of colorectal CA is increased 2 to 3 fold due to one affected first degree relative (gt50)

Moderatefamilial risk Screening by colonoscopy starting at age 40 or 10 yrs earlier than earliest case in family is reasonable

Chemo PreventionChemo Prevention Evidence that ASA NSAIDs Calcium and COX-2

inhibitors may reduce incidence of CA by reducing ofadenomas

1048707 40-50 risk reduction for developing colorectal CA regardless of location in colon age gender and race

Generally performed by RCTrsquos in patients with priorcolorectal CA followed for recurrence of adenomas

Diet fiber and antioxidant vitamins have not beenshown by RCTrsquos to decrease risk of recurrent adenomas

COX-2irsquos and Sulindac have been shown to reduce thenumber of adenomas found in FAP alone

1048707 Not effective for sporadic colon CA 1048707 Actually can cause regression of adenomas

Family History Empiric RisksFamily History Empiric RisksLifetime Risk CRC

General population in US ~2 to 6

One 1st degree relative with CRC 2-3 fold

Two 1st degree relatives with CRC 3-4 fold

1st degree relative with CRC lt50 3-4 fold

One 2nd or 3rd degree relative with CRC

~15 fold

Two 2nd degree relatives with CRC 2-3 fold

OutlineOutline Hereditary colorectal cancer syndromes Cancer family history ndash a primary tool Evaluating your patients for familial CRC risk Genetic counseling and testing for hereditary

colorectal cancer How when where to refer patients for genetic

services

Colorectal CancerColorectal Cancer

~5-8 of all cases of CRC are hereditary

~15-20 are ldquofamilialrdquomultifactorial

~75 of cases are sporadic

Characteristics of Average RiskCharacteristics of Average Risk

No well-defined threshold between sporadic and familial CRC at this time

Probably safe to include individuals with No personal risk factors or family history of CRC One 2nd or 3rd degree relative with CRC gt60 years with no

other family history of CRC

Characteristics of ldquoFamilialrdquo CRCCharacteristics of ldquoFamilialrdquo CRC

ldquoClusteringrdquo of colon cancer cases in the family (gt50 at diagnosis) without clear dominant pattern or

One close relative with CRC lt60 years and family history does not meet criteria for known hereditary CRC syndromes

Likely to be multiple low penetrant genes plus environmental factors at play

Family members warrant earlier CRC screening Starting at 40 years or 5-10 years earlier than age of diagnosis

of the youngest affected relative

Characteristics of Hereditary Characteristics of Hereditary CRCCRC

Multiple relatives with colorectal cancer One or more diagnosed at an early age (lt50)

Sequential generations affected Except in autosomal recessive syndromes

Other cancers in the family known to be associated with CRC (uterine ovarian GI)

Multiple primary tumors or polyps

Hereditary CRC SyndromesHereditary CRC Syndromes Hereditary Non-Polyposis Colorectal Cancer (HNPCC)

Variants Muir-Torre Turcot Familial Adenomatous Polyposis (FAP)

Variants Gardner Turcot Attenuated FAP APC mutation in Ashkenazi Jews

Others Multiple adenomatous polyposis syndromeMYH gene (MAP) Peutz-Jeghers syndrome (PJS) Familial Juvenile Polyposis (FJP)

HNPCC AKA ldquoLynch SyndromerdquoHNPCC AKA ldquoLynch Syndromerdquo

2-3 of all colorectal cancer cases Autosomal dominant high penetrance Typical age of CA onset is 40-50 years Multiple affected generations 60-70 right-sidedproximal CRC tumors Polyps may be present multiple primaries

common Can overlap with AFAP

HNPCCHNPCCbull Lifetime cancer risks

ndash Colorectal 80

ndash Endometrial 20-60

ndash Gastric 13-19

ndash Ovarian 9-12

ndash Biliary Tract 2

ndash Urinary Tract 4

ndash Small Bowel 1-4

ndash BrainCNS 1-3

HNPCCHNPCCClinical Diagnostic CriteriaClinical Diagnostic Criteria

Amsterdam II Criteria (3-2-1) 3 or more relatives with an HNPCC-related cancer

one of whom is a 1st degree relative of the other two 2 or more successive generations affected

1 or more cancers diagnosed before age 50

HNPCCHNPCC Caused by mutations or deletions in mismatched

repair (MMR) genes MSH2 MLH1 MSH6 (PMS2)

50 of families meeting Amsterdam II Criteria have detectable mutations

TestingScreening options Direct genetic testing of MMR genes (in select families) Initial screening of the tumor tissue by MSIIHC

MSIIHC ScreeningMSIIHC Screening Microsatellite Instability (MSI) on tumor tissue

can be used to screen for HNPCC in select cases

Immunohistochemistry (IHC) on tumor tissue

can be used to detect the presence or absence of the mismatch repair proteins (MSH2 MLH1 etc)

ldquoScreen positiverdquo individuals can be offered cancer genetic counselingassessment and targeted genetic testing

FAPFAP 1 in 10000 incidence 100rsquos to 1000rsquos of colonic adenomas by teens

Cancer risk colon gastric duodenum (periampulla) small bowel pancreas papillary thyroid childhood hepatoblastoma

7 risk of CRC by 21 yrs 93 by 50 yrs Autosomal dominant APC gene mutations Variants Gardner Turcot

FAP - SurveillanceFAP - Surveillance Colon

Annual sigmoidoscopy age 10-12 yrs Prophylactic colectomy following polyp detection with

continued surveillance of rectum ileal pouch Duodenalgastric

EGD age 25 repeat 1-3 yrs Thyroid

Annual PE age 10 Hepatoblastoma

Annual screen by abd US amp AFP from birth to 5 yrs

Attenuated FAPAttenuated FAP 20 to 100 polyps usually more proximal

Onset later than FAP average AOO = 50 Lifetime risk of CRC = 80

Extracolonic tumors occur at same rate as FAP Variant of FAP mutations in same APC gene Surveillance

annual colonoscopy starting late teens or early 20rsquos Option of subtotal colectomy

Genetic Testing FAPAFAPGenetic Testing FAPAFAP Test an affected family member first

After genetic counseling and informed consent

APC gene testing can confirm a suspected diagnosis

Family members of a person with a known APC mutation can have mutation-specific testing

Genetic testing for children at risk for FAP can be considered before beginning colon screening

APC gene mutation inAPC gene mutation inAshkenazi JewsAshkenazi Jews

Missense mutation (I1307K) associated with increased risk of CRC and adenomas in Ashkenazi Jews (AJ)

Found in 6 of the general AJ population

12 of AJs with CRC

29 of AJs with CRC and a positive family history

Lifetime risk of CRC in mutation carrier is 10-20

Screening colonoscopy every 2-5 yrs starting at 35 yrs

MAP syndromeMYH geneMAP syndromeMYH gene Multiple adenomatous polyposis (MAP) syndrome

Autosomal recessive mutations in the MYH gene Median number of polyps = 55 Mean age of polyp diagnosis = 30-50 years Polyps mainly small mildly dysplastic tubular adenomas Some

tubulovillous hyperplastic serrated adenomas microadenomas

30 of individuals with 15-100 polyps have homozygous mutations in the MYH gene

Genetic testing should be offered if gt15 polyps (and APC gene testing negative)

Peutz-Jeghers SyndromePeutz-Jeghers Syndrome lt1 of all CRC cases Hamartomatous polyps of GI tract as early as 1st decade Mucocutaneous hyper pigmentation

lips mouth buccal mucosa fingers Usually seen in children lt 5 yrs

Cancer risk colon small intestine stomach pancreas breast ovaries uterus testes

lungs kidneys Mutations in STK11 gene

found in 70 of familial cases and 30-70 of sporadic cases

Familial Juvenile PolyposisFamilial Juvenile Polyposis

lt1 of all CRC cases

Autosomal dominant

5 or more juvenile polyps in colon or GI tract

Appear in 1st or 2nd decade

50 lifetime risk of CRC AOO in 30rsquos

Increased risk gastric GI pancreatic CA

~50 of cases have mutations in either the MADH4 or BMPR1A genes

Family Health HistoryFamily Health History

ldquoThe family tree has become the most important genetic test of all The more you know the more tools you have to practice preventive medicinerdquo

Donna Russo Certified Genetic Counselor NY Presbyterian-Columbia Hospital

Goal ClassificationGoal ClassificationAssessment Risk Classification Intervention

Family History

Average

Moderate

(ldquoFamilialrdquo)

HighGenetic

Personalized prevention recommendations

Standard prevention recommendations

Referral for genetic evaluation with personalized prevention recommendations

Consider Genetics Referral forConsider Genetics Referral for

Two or more family members with CRC at least one lt50

Three or more family members wCRC any age

Patient with colon cancer before 40 yrs

Endometrial cancer and family history of CRC lt50

Persons with more than one primary CRC lt50 yrs or with both endometrial CA and CRC

Family or personal history of CRC and one or more 1st degree relative with an HNPCC-related cancer one diagnosed lt50 yrs

Same side of family

Consider Genetics Referral forConsider Genetics Referral for

MSI andor IHC tumor results suspicious for HNPCC

Autosomal dominant pattern of cancers in the family

Persons with 15 or more adenomatous colorectal polyps

Persons with multiple hamartomatous or juvenile GI polyps

Persons with a family history of a known hereditary cancer syndrome

CRC Risk ManagementCRC Risk Management

Average Risk

1 No family history CRC OR2 One 2nd or 3rd degree relative with CRC

FOBT annually + flex sig every 5 years OR Colonoscopy every 10 years OR DCBE every 5 years

Age to Begin50 years

CRC Risk ManagementCRC Risk ManagementModerateFamily history Two 1st degree relatives with CRC any age

or one 1st degree relative with CRC lt 60- Colonoscopy every 5 yrs

One 1st degree relative with CRC gt60 or two 2nd degree relatives with CRC any age- Average risk screening

Or 5-10 yrs earlier than earliest case in family

Age to begin

40 years

40 years

CRC Risk ManagementCRC Risk Management

Age to Begin

HNPCC or suspected HNPCC 20-25 years 1 Colonoscopy every 1-2 yrs

2 Genetic counseling consider genetic testing

FAP or suspected FAP 10-12 years 1 Flex sig or colonoscopy every1-2 yrs

2 Genetic counseling consider genetic testing

Case 1 JoanCase 1 Joan Joan age 38 was recently diagnosed with

endometrial cancer Family history reveals

1 Paternal grandmother endometrial cancer age 50 2 Paternal uncle colon cancer age 48 3 Father colonoscopy at age 50 four adenomatous

polyps removed 4 No other significant history 5 Both sides of the family are Northern European

Caucasian

Pedigree Case 1Pedigree Case 1French Irish Scottish German English

88 yr

61 yr 63 yr

4 polyps

50 yrs 38 yr

35 yrDx 38

8 yr10 yr

CRC Dx 48

Dx 50

KEYKEY

Endometrial CA

Colorectal CA

Adenomatous Polyps

Case 1 AssessmentCase 1 Assessment Joan meets Amsterdam II Criteria and is at risk for HNPCC

Refer to genetics for cancer genetic counseling and discussion of genetic testing for HNPCC

Testing options

1 Direct gene testing of MLH1 and MSH2 OR

2 MSIIHC screening of tumor tissue with gene sequencing if MSI positive

Case 2 TedCase 2 Ted Ted is 30 and wants a colonoscopy because his mother

was just diagnosed with colon cancer after routine screening at age 54 Family history reveals

1 Paternal grandfather died of CRC at age 79

2 No hx of endometrial ovarian small bowel or ureterkidney cancer on either side of family

3 Two maternal aunts cervical cancer at ages 30 amp 34

4 Maternal grandmother breast cancer age 85

Pedigree Case 2Pedigree Case 2Italian Irish German

KEY

CRC

Breast CA

Cervical CA

84

d 58 MIBrCa 85 yrs

d87

55 58 60

Colon CA 54 yrs

Cervical CA 30 yrs

Cervical CA 32 yrs

34 yrs 30 yrs

CRC 79 d82

56

Case 2 TedCase 2 Ted Verify Diagnoses Obtain and review pathology reports on

all reported cancers whenever possible

If diagnoses are correct Ted has no family history indicative of a known colon cancer syndrome (HNPCC FAP other)

Tedrsquos lifetime risk of colorectal CA is increased 2 to 3 fold due to one affected first degree relative (gt50)

Moderatefamilial risk Screening by colonoscopy starting at age 40 or 10 yrs earlier than earliest case in family is reasonable

Chemo PreventionChemo Prevention Evidence that ASA NSAIDs Calcium and COX-2

inhibitors may reduce incidence of CA by reducing ofadenomas

1048707 40-50 risk reduction for developing colorectal CA regardless of location in colon age gender and race

Generally performed by RCTrsquos in patients with priorcolorectal CA followed for recurrence of adenomas

Diet fiber and antioxidant vitamins have not beenshown by RCTrsquos to decrease risk of recurrent adenomas

COX-2irsquos and Sulindac have been shown to reduce thenumber of adenomas found in FAP alone

1048707 Not effective for sporadic colon CA 1048707 Actually can cause regression of adenomas

OutlineOutline Hereditary colorectal cancer syndromes Cancer family history ndash a primary tool Evaluating your patients for familial CRC risk Genetic counseling and testing for hereditary

colorectal cancer How when where to refer patients for genetic

services

Colorectal CancerColorectal Cancer

~5-8 of all cases of CRC are hereditary

~15-20 are ldquofamilialrdquomultifactorial

~75 of cases are sporadic

Characteristics of Average RiskCharacteristics of Average Risk

No well-defined threshold between sporadic and familial CRC at this time

Probably safe to include individuals with No personal risk factors or family history of CRC One 2nd or 3rd degree relative with CRC gt60 years with no

other family history of CRC

Characteristics of ldquoFamilialrdquo CRCCharacteristics of ldquoFamilialrdquo CRC

ldquoClusteringrdquo of colon cancer cases in the family (gt50 at diagnosis) without clear dominant pattern or

One close relative with CRC lt60 years and family history does not meet criteria for known hereditary CRC syndromes

Likely to be multiple low penetrant genes plus environmental factors at play

Family members warrant earlier CRC screening Starting at 40 years or 5-10 years earlier than age of diagnosis

of the youngest affected relative

Characteristics of Hereditary Characteristics of Hereditary CRCCRC

Multiple relatives with colorectal cancer One or more diagnosed at an early age (lt50)

Sequential generations affected Except in autosomal recessive syndromes

Other cancers in the family known to be associated with CRC (uterine ovarian GI)

Multiple primary tumors or polyps

Hereditary CRC SyndromesHereditary CRC Syndromes Hereditary Non-Polyposis Colorectal Cancer (HNPCC)

Variants Muir-Torre Turcot Familial Adenomatous Polyposis (FAP)

Variants Gardner Turcot Attenuated FAP APC mutation in Ashkenazi Jews

Others Multiple adenomatous polyposis syndromeMYH gene (MAP) Peutz-Jeghers syndrome (PJS) Familial Juvenile Polyposis (FJP)

HNPCC AKA ldquoLynch SyndromerdquoHNPCC AKA ldquoLynch Syndromerdquo

2-3 of all colorectal cancer cases Autosomal dominant high penetrance Typical age of CA onset is 40-50 years Multiple affected generations 60-70 right-sidedproximal CRC tumors Polyps may be present multiple primaries

common Can overlap with AFAP

HNPCCHNPCCbull Lifetime cancer risks

ndash Colorectal 80

ndash Endometrial 20-60

ndash Gastric 13-19

ndash Ovarian 9-12

ndash Biliary Tract 2

ndash Urinary Tract 4

ndash Small Bowel 1-4

ndash BrainCNS 1-3

HNPCCHNPCCClinical Diagnostic CriteriaClinical Diagnostic Criteria

Amsterdam II Criteria (3-2-1) 3 or more relatives with an HNPCC-related cancer

one of whom is a 1st degree relative of the other two 2 or more successive generations affected

1 or more cancers diagnosed before age 50

HNPCCHNPCC Caused by mutations or deletions in mismatched

repair (MMR) genes MSH2 MLH1 MSH6 (PMS2)

50 of families meeting Amsterdam II Criteria have detectable mutations

TestingScreening options Direct genetic testing of MMR genes (in select families) Initial screening of the tumor tissue by MSIIHC

MSIIHC ScreeningMSIIHC Screening Microsatellite Instability (MSI) on tumor tissue

can be used to screen for HNPCC in select cases

Immunohistochemistry (IHC) on tumor tissue

can be used to detect the presence or absence of the mismatch repair proteins (MSH2 MLH1 etc)

ldquoScreen positiverdquo individuals can be offered cancer genetic counselingassessment and targeted genetic testing

FAPFAP 1 in 10000 incidence 100rsquos to 1000rsquos of colonic adenomas by teens

Cancer risk colon gastric duodenum (periampulla) small bowel pancreas papillary thyroid childhood hepatoblastoma

7 risk of CRC by 21 yrs 93 by 50 yrs Autosomal dominant APC gene mutations Variants Gardner Turcot

FAP - SurveillanceFAP - Surveillance Colon

Annual sigmoidoscopy age 10-12 yrs Prophylactic colectomy following polyp detection with

continued surveillance of rectum ileal pouch Duodenalgastric

EGD age 25 repeat 1-3 yrs Thyroid

Annual PE age 10 Hepatoblastoma

Annual screen by abd US amp AFP from birth to 5 yrs

Attenuated FAPAttenuated FAP 20 to 100 polyps usually more proximal

Onset later than FAP average AOO = 50 Lifetime risk of CRC = 80

Extracolonic tumors occur at same rate as FAP Variant of FAP mutations in same APC gene Surveillance

annual colonoscopy starting late teens or early 20rsquos Option of subtotal colectomy

Genetic Testing FAPAFAPGenetic Testing FAPAFAP Test an affected family member first

After genetic counseling and informed consent

APC gene testing can confirm a suspected diagnosis

Family members of a person with a known APC mutation can have mutation-specific testing

Genetic testing for children at risk for FAP can be considered before beginning colon screening

APC gene mutation inAPC gene mutation inAshkenazi JewsAshkenazi Jews

Missense mutation (I1307K) associated with increased risk of CRC and adenomas in Ashkenazi Jews (AJ)

Found in 6 of the general AJ population

12 of AJs with CRC

29 of AJs with CRC and a positive family history

Lifetime risk of CRC in mutation carrier is 10-20

Screening colonoscopy every 2-5 yrs starting at 35 yrs

MAP syndromeMYH geneMAP syndromeMYH gene Multiple adenomatous polyposis (MAP) syndrome

Autosomal recessive mutations in the MYH gene Median number of polyps = 55 Mean age of polyp diagnosis = 30-50 years Polyps mainly small mildly dysplastic tubular adenomas Some

tubulovillous hyperplastic serrated adenomas microadenomas

30 of individuals with 15-100 polyps have homozygous mutations in the MYH gene

Genetic testing should be offered if gt15 polyps (and APC gene testing negative)

Peutz-Jeghers SyndromePeutz-Jeghers Syndrome lt1 of all CRC cases Hamartomatous polyps of GI tract as early as 1st decade Mucocutaneous hyper pigmentation

lips mouth buccal mucosa fingers Usually seen in children lt 5 yrs

Cancer risk colon small intestine stomach pancreas breast ovaries uterus testes

lungs kidneys Mutations in STK11 gene

found in 70 of familial cases and 30-70 of sporadic cases

Familial Juvenile PolyposisFamilial Juvenile Polyposis

lt1 of all CRC cases

Autosomal dominant

5 or more juvenile polyps in colon or GI tract

Appear in 1st or 2nd decade

50 lifetime risk of CRC AOO in 30rsquos

Increased risk gastric GI pancreatic CA

~50 of cases have mutations in either the MADH4 or BMPR1A genes

Family Health HistoryFamily Health History

ldquoThe family tree has become the most important genetic test of all The more you know the more tools you have to practice preventive medicinerdquo

Donna Russo Certified Genetic Counselor NY Presbyterian-Columbia Hospital

Goal ClassificationGoal ClassificationAssessment Risk Classification Intervention

Family History

Average

Moderate

(ldquoFamilialrdquo)

HighGenetic

Personalized prevention recommendations

Standard prevention recommendations

Referral for genetic evaluation with personalized prevention recommendations

Consider Genetics Referral forConsider Genetics Referral for

Two or more family members with CRC at least one lt50

Three or more family members wCRC any age

Patient with colon cancer before 40 yrs

Endometrial cancer and family history of CRC lt50

Persons with more than one primary CRC lt50 yrs or with both endometrial CA and CRC

Family or personal history of CRC and one or more 1st degree relative with an HNPCC-related cancer one diagnosed lt50 yrs

Same side of family

Consider Genetics Referral forConsider Genetics Referral for

MSI andor IHC tumor results suspicious for HNPCC

Autosomal dominant pattern of cancers in the family

Persons with 15 or more adenomatous colorectal polyps

Persons with multiple hamartomatous or juvenile GI polyps

Persons with a family history of a known hereditary cancer syndrome

CRC Risk ManagementCRC Risk Management

Average Risk

1 No family history CRC OR2 One 2nd or 3rd degree relative with CRC

FOBT annually + flex sig every 5 years OR Colonoscopy every 10 years OR DCBE every 5 years

Age to Begin50 years

CRC Risk ManagementCRC Risk ManagementModerateFamily history Two 1st degree relatives with CRC any age

or one 1st degree relative with CRC lt 60- Colonoscopy every 5 yrs

One 1st degree relative with CRC gt60 or two 2nd degree relatives with CRC any age- Average risk screening

Or 5-10 yrs earlier than earliest case in family

Age to begin

40 years

40 years

CRC Risk ManagementCRC Risk Management

Age to Begin

HNPCC or suspected HNPCC 20-25 years 1 Colonoscopy every 1-2 yrs

2 Genetic counseling consider genetic testing

FAP or suspected FAP 10-12 years 1 Flex sig or colonoscopy every1-2 yrs

2 Genetic counseling consider genetic testing

Case 1 JoanCase 1 Joan Joan age 38 was recently diagnosed with

endometrial cancer Family history reveals

1 Paternal grandmother endometrial cancer age 50 2 Paternal uncle colon cancer age 48 3 Father colonoscopy at age 50 four adenomatous

polyps removed 4 No other significant history 5 Both sides of the family are Northern European

Caucasian

Pedigree Case 1Pedigree Case 1French Irish Scottish German English

88 yr

61 yr 63 yr

4 polyps

50 yrs 38 yr

35 yrDx 38

8 yr10 yr

CRC Dx 48

Dx 50

KEYKEY

Endometrial CA

Colorectal CA

Adenomatous Polyps

Case 1 AssessmentCase 1 Assessment Joan meets Amsterdam II Criteria and is at risk for HNPCC

Refer to genetics for cancer genetic counseling and discussion of genetic testing for HNPCC

Testing options

1 Direct gene testing of MLH1 and MSH2 OR

2 MSIIHC screening of tumor tissue with gene sequencing if MSI positive

Case 2 TedCase 2 Ted Ted is 30 and wants a colonoscopy because his mother

was just diagnosed with colon cancer after routine screening at age 54 Family history reveals

1 Paternal grandfather died of CRC at age 79

2 No hx of endometrial ovarian small bowel or ureterkidney cancer on either side of family

3 Two maternal aunts cervical cancer at ages 30 amp 34

4 Maternal grandmother breast cancer age 85

Pedigree Case 2Pedigree Case 2Italian Irish German

KEY

CRC

Breast CA

Cervical CA

84

d 58 MIBrCa 85 yrs

d87

55 58 60

Colon CA 54 yrs

Cervical CA 30 yrs

Cervical CA 32 yrs

34 yrs 30 yrs

CRC 79 d82

56

Case 2 TedCase 2 Ted Verify Diagnoses Obtain and review pathology reports on

all reported cancers whenever possible

If diagnoses are correct Ted has no family history indicative of a known colon cancer syndrome (HNPCC FAP other)

Tedrsquos lifetime risk of colorectal CA is increased 2 to 3 fold due to one affected first degree relative (gt50)

Moderatefamilial risk Screening by colonoscopy starting at age 40 or 10 yrs earlier than earliest case in family is reasonable

Chemo PreventionChemo Prevention Evidence that ASA NSAIDs Calcium and COX-2

inhibitors may reduce incidence of CA by reducing ofadenomas

1048707 40-50 risk reduction for developing colorectal CA regardless of location in colon age gender and race

Generally performed by RCTrsquos in patients with priorcolorectal CA followed for recurrence of adenomas

Diet fiber and antioxidant vitamins have not beenshown by RCTrsquos to decrease risk of recurrent adenomas

COX-2irsquos and Sulindac have been shown to reduce thenumber of adenomas found in FAP alone

1048707 Not effective for sporadic colon CA 1048707 Actually can cause regression of adenomas

Colorectal CancerColorectal Cancer

~5-8 of all cases of CRC are hereditary

~15-20 are ldquofamilialrdquomultifactorial

~75 of cases are sporadic

Characteristics of Average RiskCharacteristics of Average Risk

No well-defined threshold between sporadic and familial CRC at this time

Probably safe to include individuals with No personal risk factors or family history of CRC One 2nd or 3rd degree relative with CRC gt60 years with no

other family history of CRC

Characteristics of ldquoFamilialrdquo CRCCharacteristics of ldquoFamilialrdquo CRC

ldquoClusteringrdquo of colon cancer cases in the family (gt50 at diagnosis) without clear dominant pattern or

One close relative with CRC lt60 years and family history does not meet criteria for known hereditary CRC syndromes

Likely to be multiple low penetrant genes plus environmental factors at play

Family members warrant earlier CRC screening Starting at 40 years or 5-10 years earlier than age of diagnosis

of the youngest affected relative

Characteristics of Hereditary Characteristics of Hereditary CRCCRC

Multiple relatives with colorectal cancer One or more diagnosed at an early age (lt50)

Sequential generations affected Except in autosomal recessive syndromes

Other cancers in the family known to be associated with CRC (uterine ovarian GI)

Multiple primary tumors or polyps

Hereditary CRC SyndromesHereditary CRC Syndromes Hereditary Non-Polyposis Colorectal Cancer (HNPCC)

Variants Muir-Torre Turcot Familial Adenomatous Polyposis (FAP)

Variants Gardner Turcot Attenuated FAP APC mutation in Ashkenazi Jews

Others Multiple adenomatous polyposis syndromeMYH gene (MAP) Peutz-Jeghers syndrome (PJS) Familial Juvenile Polyposis (FJP)

HNPCC AKA ldquoLynch SyndromerdquoHNPCC AKA ldquoLynch Syndromerdquo

2-3 of all colorectal cancer cases Autosomal dominant high penetrance Typical age of CA onset is 40-50 years Multiple affected generations 60-70 right-sidedproximal CRC tumors Polyps may be present multiple primaries

common Can overlap with AFAP

HNPCCHNPCCbull Lifetime cancer risks

ndash Colorectal 80

ndash Endometrial 20-60

ndash Gastric 13-19

ndash Ovarian 9-12

ndash Biliary Tract 2

ndash Urinary Tract 4

ndash Small Bowel 1-4

ndash BrainCNS 1-3

HNPCCHNPCCClinical Diagnostic CriteriaClinical Diagnostic Criteria

Amsterdam II Criteria (3-2-1) 3 or more relatives with an HNPCC-related cancer

one of whom is a 1st degree relative of the other two 2 or more successive generations affected

1 or more cancers diagnosed before age 50

HNPCCHNPCC Caused by mutations or deletions in mismatched

repair (MMR) genes MSH2 MLH1 MSH6 (PMS2)

50 of families meeting Amsterdam II Criteria have detectable mutations

TestingScreening options Direct genetic testing of MMR genes (in select families) Initial screening of the tumor tissue by MSIIHC

MSIIHC ScreeningMSIIHC Screening Microsatellite Instability (MSI) on tumor tissue

can be used to screen for HNPCC in select cases

Immunohistochemistry (IHC) on tumor tissue

can be used to detect the presence or absence of the mismatch repair proteins (MSH2 MLH1 etc)

ldquoScreen positiverdquo individuals can be offered cancer genetic counselingassessment and targeted genetic testing

FAPFAP 1 in 10000 incidence 100rsquos to 1000rsquos of colonic adenomas by teens

Cancer risk colon gastric duodenum (periampulla) small bowel pancreas papillary thyroid childhood hepatoblastoma

7 risk of CRC by 21 yrs 93 by 50 yrs Autosomal dominant APC gene mutations Variants Gardner Turcot

FAP - SurveillanceFAP - Surveillance Colon

Annual sigmoidoscopy age 10-12 yrs Prophylactic colectomy following polyp detection with

continued surveillance of rectum ileal pouch Duodenalgastric

EGD age 25 repeat 1-3 yrs Thyroid

Annual PE age 10 Hepatoblastoma

Annual screen by abd US amp AFP from birth to 5 yrs

Attenuated FAPAttenuated FAP 20 to 100 polyps usually more proximal

Onset later than FAP average AOO = 50 Lifetime risk of CRC = 80

Extracolonic tumors occur at same rate as FAP Variant of FAP mutations in same APC gene Surveillance

annual colonoscopy starting late teens or early 20rsquos Option of subtotal colectomy

Genetic Testing FAPAFAPGenetic Testing FAPAFAP Test an affected family member first

After genetic counseling and informed consent

APC gene testing can confirm a suspected diagnosis

Family members of a person with a known APC mutation can have mutation-specific testing

Genetic testing for children at risk for FAP can be considered before beginning colon screening

APC gene mutation inAPC gene mutation inAshkenazi JewsAshkenazi Jews

Missense mutation (I1307K) associated with increased risk of CRC and adenomas in Ashkenazi Jews (AJ)

Found in 6 of the general AJ population

12 of AJs with CRC

29 of AJs with CRC and a positive family history

Lifetime risk of CRC in mutation carrier is 10-20

Screening colonoscopy every 2-5 yrs starting at 35 yrs

MAP syndromeMYH geneMAP syndromeMYH gene Multiple adenomatous polyposis (MAP) syndrome

Autosomal recessive mutations in the MYH gene Median number of polyps = 55 Mean age of polyp diagnosis = 30-50 years Polyps mainly small mildly dysplastic tubular adenomas Some

tubulovillous hyperplastic serrated adenomas microadenomas

30 of individuals with 15-100 polyps have homozygous mutations in the MYH gene

Genetic testing should be offered if gt15 polyps (and APC gene testing negative)

Peutz-Jeghers SyndromePeutz-Jeghers Syndrome lt1 of all CRC cases Hamartomatous polyps of GI tract as early as 1st decade Mucocutaneous hyper pigmentation

lips mouth buccal mucosa fingers Usually seen in children lt 5 yrs

Cancer risk colon small intestine stomach pancreas breast ovaries uterus testes

lungs kidneys Mutations in STK11 gene

found in 70 of familial cases and 30-70 of sporadic cases

Familial Juvenile PolyposisFamilial Juvenile Polyposis

lt1 of all CRC cases

Autosomal dominant

5 or more juvenile polyps in colon or GI tract

Appear in 1st or 2nd decade

50 lifetime risk of CRC AOO in 30rsquos

Increased risk gastric GI pancreatic CA

~50 of cases have mutations in either the MADH4 or BMPR1A genes

Family Health HistoryFamily Health History

ldquoThe family tree has become the most important genetic test of all The more you know the more tools you have to practice preventive medicinerdquo

Donna Russo Certified Genetic Counselor NY Presbyterian-Columbia Hospital

Goal ClassificationGoal ClassificationAssessment Risk Classification Intervention

Family History

Average

Moderate

(ldquoFamilialrdquo)

HighGenetic

Personalized prevention recommendations

Standard prevention recommendations

Referral for genetic evaluation with personalized prevention recommendations

Consider Genetics Referral forConsider Genetics Referral for

Two or more family members with CRC at least one lt50

Three or more family members wCRC any age

Patient with colon cancer before 40 yrs

Endometrial cancer and family history of CRC lt50

Persons with more than one primary CRC lt50 yrs or with both endometrial CA and CRC

Family or personal history of CRC and one or more 1st degree relative with an HNPCC-related cancer one diagnosed lt50 yrs

Same side of family

Consider Genetics Referral forConsider Genetics Referral for

MSI andor IHC tumor results suspicious for HNPCC

Autosomal dominant pattern of cancers in the family

Persons with 15 or more adenomatous colorectal polyps

Persons with multiple hamartomatous or juvenile GI polyps

Persons with a family history of a known hereditary cancer syndrome

CRC Risk ManagementCRC Risk Management

Average Risk

1 No family history CRC OR2 One 2nd or 3rd degree relative with CRC

FOBT annually + flex sig every 5 years OR Colonoscopy every 10 years OR DCBE every 5 years

Age to Begin50 years

CRC Risk ManagementCRC Risk ManagementModerateFamily history Two 1st degree relatives with CRC any age

or one 1st degree relative with CRC lt 60- Colonoscopy every 5 yrs

One 1st degree relative with CRC gt60 or two 2nd degree relatives with CRC any age- Average risk screening

Or 5-10 yrs earlier than earliest case in family

Age to begin

40 years

40 years

CRC Risk ManagementCRC Risk Management

Age to Begin

HNPCC or suspected HNPCC 20-25 years 1 Colonoscopy every 1-2 yrs

2 Genetic counseling consider genetic testing

FAP or suspected FAP 10-12 years 1 Flex sig or colonoscopy every1-2 yrs

2 Genetic counseling consider genetic testing

Case 1 JoanCase 1 Joan Joan age 38 was recently diagnosed with

endometrial cancer Family history reveals

1 Paternal grandmother endometrial cancer age 50 2 Paternal uncle colon cancer age 48 3 Father colonoscopy at age 50 four adenomatous

polyps removed 4 No other significant history 5 Both sides of the family are Northern European

Caucasian

Pedigree Case 1Pedigree Case 1French Irish Scottish German English

88 yr

61 yr 63 yr

4 polyps

50 yrs 38 yr

35 yrDx 38

8 yr10 yr

CRC Dx 48

Dx 50

KEYKEY

Endometrial CA

Colorectal CA

Adenomatous Polyps

Case 1 AssessmentCase 1 Assessment Joan meets Amsterdam II Criteria and is at risk for HNPCC

Refer to genetics for cancer genetic counseling and discussion of genetic testing for HNPCC

Testing options

1 Direct gene testing of MLH1 and MSH2 OR

2 MSIIHC screening of tumor tissue with gene sequencing if MSI positive

Case 2 TedCase 2 Ted Ted is 30 and wants a colonoscopy because his mother

was just diagnosed with colon cancer after routine screening at age 54 Family history reveals

1 Paternal grandfather died of CRC at age 79

2 No hx of endometrial ovarian small bowel or ureterkidney cancer on either side of family

3 Two maternal aunts cervical cancer at ages 30 amp 34

4 Maternal grandmother breast cancer age 85

Pedigree Case 2Pedigree Case 2Italian Irish German

KEY

CRC

Breast CA

Cervical CA

84

d 58 MIBrCa 85 yrs

d87

55 58 60

Colon CA 54 yrs

Cervical CA 30 yrs

Cervical CA 32 yrs

34 yrs 30 yrs

CRC 79 d82

56

Case 2 TedCase 2 Ted Verify Diagnoses Obtain and review pathology reports on

all reported cancers whenever possible

If diagnoses are correct Ted has no family history indicative of a known colon cancer syndrome (HNPCC FAP other)

Tedrsquos lifetime risk of colorectal CA is increased 2 to 3 fold due to one affected first degree relative (gt50)

Moderatefamilial risk Screening by colonoscopy starting at age 40 or 10 yrs earlier than earliest case in family is reasonable

Chemo PreventionChemo Prevention Evidence that ASA NSAIDs Calcium and COX-2

inhibitors may reduce incidence of CA by reducing ofadenomas

1048707 40-50 risk reduction for developing colorectal CA regardless of location in colon age gender and race

Generally performed by RCTrsquos in patients with priorcolorectal CA followed for recurrence of adenomas

Diet fiber and antioxidant vitamins have not beenshown by RCTrsquos to decrease risk of recurrent adenomas

COX-2irsquos and Sulindac have been shown to reduce thenumber of adenomas found in FAP alone

1048707 Not effective for sporadic colon CA 1048707 Actually can cause regression of adenomas

Characteristics of Average RiskCharacteristics of Average Risk

No well-defined threshold between sporadic and familial CRC at this time

Probably safe to include individuals with No personal risk factors or family history of CRC One 2nd or 3rd degree relative with CRC gt60 years with no

other family history of CRC

Characteristics of ldquoFamilialrdquo CRCCharacteristics of ldquoFamilialrdquo CRC

ldquoClusteringrdquo of colon cancer cases in the family (gt50 at diagnosis) without clear dominant pattern or

One close relative with CRC lt60 years and family history does not meet criteria for known hereditary CRC syndromes

Likely to be multiple low penetrant genes plus environmental factors at play

Family members warrant earlier CRC screening Starting at 40 years or 5-10 years earlier than age of diagnosis

of the youngest affected relative

Characteristics of Hereditary Characteristics of Hereditary CRCCRC

Multiple relatives with colorectal cancer One or more diagnosed at an early age (lt50)

Sequential generations affected Except in autosomal recessive syndromes

Other cancers in the family known to be associated with CRC (uterine ovarian GI)

Multiple primary tumors or polyps

Hereditary CRC SyndromesHereditary CRC Syndromes Hereditary Non-Polyposis Colorectal Cancer (HNPCC)

Variants Muir-Torre Turcot Familial Adenomatous Polyposis (FAP)

Variants Gardner Turcot Attenuated FAP APC mutation in Ashkenazi Jews

Others Multiple adenomatous polyposis syndromeMYH gene (MAP) Peutz-Jeghers syndrome (PJS) Familial Juvenile Polyposis (FJP)

HNPCC AKA ldquoLynch SyndromerdquoHNPCC AKA ldquoLynch Syndromerdquo

2-3 of all colorectal cancer cases Autosomal dominant high penetrance Typical age of CA onset is 40-50 years Multiple affected generations 60-70 right-sidedproximal CRC tumors Polyps may be present multiple primaries

common Can overlap with AFAP

HNPCCHNPCCbull Lifetime cancer risks

ndash Colorectal 80

ndash Endometrial 20-60

ndash Gastric 13-19

ndash Ovarian 9-12

ndash Biliary Tract 2

ndash Urinary Tract 4

ndash Small Bowel 1-4

ndash BrainCNS 1-3

HNPCCHNPCCClinical Diagnostic CriteriaClinical Diagnostic Criteria

Amsterdam II Criteria (3-2-1) 3 or more relatives with an HNPCC-related cancer

one of whom is a 1st degree relative of the other two 2 or more successive generations affected

1 or more cancers diagnosed before age 50

HNPCCHNPCC Caused by mutations or deletions in mismatched

repair (MMR) genes MSH2 MLH1 MSH6 (PMS2)

50 of families meeting Amsterdam II Criteria have detectable mutations

TestingScreening options Direct genetic testing of MMR genes (in select families) Initial screening of the tumor tissue by MSIIHC

MSIIHC ScreeningMSIIHC Screening Microsatellite Instability (MSI) on tumor tissue

can be used to screen for HNPCC in select cases

Immunohistochemistry (IHC) on tumor tissue

can be used to detect the presence or absence of the mismatch repair proteins (MSH2 MLH1 etc)

ldquoScreen positiverdquo individuals can be offered cancer genetic counselingassessment and targeted genetic testing

FAPFAP 1 in 10000 incidence 100rsquos to 1000rsquos of colonic adenomas by teens

Cancer risk colon gastric duodenum (periampulla) small bowel pancreas papillary thyroid childhood hepatoblastoma

7 risk of CRC by 21 yrs 93 by 50 yrs Autosomal dominant APC gene mutations Variants Gardner Turcot

FAP - SurveillanceFAP - Surveillance Colon

Annual sigmoidoscopy age 10-12 yrs Prophylactic colectomy following polyp detection with

continued surveillance of rectum ileal pouch Duodenalgastric

EGD age 25 repeat 1-3 yrs Thyroid

Annual PE age 10 Hepatoblastoma

Annual screen by abd US amp AFP from birth to 5 yrs

Attenuated FAPAttenuated FAP 20 to 100 polyps usually more proximal

Onset later than FAP average AOO = 50 Lifetime risk of CRC = 80

Extracolonic tumors occur at same rate as FAP Variant of FAP mutations in same APC gene Surveillance

annual colonoscopy starting late teens or early 20rsquos Option of subtotal colectomy

Genetic Testing FAPAFAPGenetic Testing FAPAFAP Test an affected family member first

After genetic counseling and informed consent

APC gene testing can confirm a suspected diagnosis

Family members of a person with a known APC mutation can have mutation-specific testing

Genetic testing for children at risk for FAP can be considered before beginning colon screening

APC gene mutation inAPC gene mutation inAshkenazi JewsAshkenazi Jews

Missense mutation (I1307K) associated with increased risk of CRC and adenomas in Ashkenazi Jews (AJ)

Found in 6 of the general AJ population

12 of AJs with CRC

29 of AJs with CRC and a positive family history

Lifetime risk of CRC in mutation carrier is 10-20

Screening colonoscopy every 2-5 yrs starting at 35 yrs

MAP syndromeMYH geneMAP syndromeMYH gene Multiple adenomatous polyposis (MAP) syndrome

Autosomal recessive mutations in the MYH gene Median number of polyps = 55 Mean age of polyp diagnosis = 30-50 years Polyps mainly small mildly dysplastic tubular adenomas Some

tubulovillous hyperplastic serrated adenomas microadenomas

30 of individuals with 15-100 polyps have homozygous mutations in the MYH gene

Genetic testing should be offered if gt15 polyps (and APC gene testing negative)

Peutz-Jeghers SyndromePeutz-Jeghers Syndrome lt1 of all CRC cases Hamartomatous polyps of GI tract as early as 1st decade Mucocutaneous hyper pigmentation

lips mouth buccal mucosa fingers Usually seen in children lt 5 yrs

Cancer risk colon small intestine stomach pancreas breast ovaries uterus testes

lungs kidneys Mutations in STK11 gene

found in 70 of familial cases and 30-70 of sporadic cases

Familial Juvenile PolyposisFamilial Juvenile Polyposis

lt1 of all CRC cases

Autosomal dominant

5 or more juvenile polyps in colon or GI tract

Appear in 1st or 2nd decade

50 lifetime risk of CRC AOO in 30rsquos

Increased risk gastric GI pancreatic CA

~50 of cases have mutations in either the MADH4 or BMPR1A genes

Family Health HistoryFamily Health History

ldquoThe family tree has become the most important genetic test of all The more you know the more tools you have to practice preventive medicinerdquo

Donna Russo Certified Genetic Counselor NY Presbyterian-Columbia Hospital

Goal ClassificationGoal ClassificationAssessment Risk Classification Intervention

Family History

Average

Moderate

(ldquoFamilialrdquo)

HighGenetic

Personalized prevention recommendations

Standard prevention recommendations

Referral for genetic evaluation with personalized prevention recommendations

Consider Genetics Referral forConsider Genetics Referral for

Two or more family members with CRC at least one lt50

Three or more family members wCRC any age

Patient with colon cancer before 40 yrs

Endometrial cancer and family history of CRC lt50

Persons with more than one primary CRC lt50 yrs or with both endometrial CA and CRC

Family or personal history of CRC and one or more 1st degree relative with an HNPCC-related cancer one diagnosed lt50 yrs

Same side of family

Consider Genetics Referral forConsider Genetics Referral for

MSI andor IHC tumor results suspicious for HNPCC

Autosomal dominant pattern of cancers in the family

Persons with 15 or more adenomatous colorectal polyps

Persons with multiple hamartomatous or juvenile GI polyps

Persons with a family history of a known hereditary cancer syndrome

CRC Risk ManagementCRC Risk Management

Average Risk

1 No family history CRC OR2 One 2nd or 3rd degree relative with CRC

FOBT annually + flex sig every 5 years OR Colonoscopy every 10 years OR DCBE every 5 years

Age to Begin50 years

CRC Risk ManagementCRC Risk ManagementModerateFamily history Two 1st degree relatives with CRC any age

or one 1st degree relative with CRC lt 60- Colonoscopy every 5 yrs

One 1st degree relative with CRC gt60 or two 2nd degree relatives with CRC any age- Average risk screening

Or 5-10 yrs earlier than earliest case in family

Age to begin

40 years

40 years

CRC Risk ManagementCRC Risk Management

Age to Begin

HNPCC or suspected HNPCC 20-25 years 1 Colonoscopy every 1-2 yrs

2 Genetic counseling consider genetic testing

FAP or suspected FAP 10-12 years 1 Flex sig or colonoscopy every1-2 yrs

2 Genetic counseling consider genetic testing

Case 1 JoanCase 1 Joan Joan age 38 was recently diagnosed with

endometrial cancer Family history reveals

1 Paternal grandmother endometrial cancer age 50 2 Paternal uncle colon cancer age 48 3 Father colonoscopy at age 50 four adenomatous

polyps removed 4 No other significant history 5 Both sides of the family are Northern European

Caucasian

Pedigree Case 1Pedigree Case 1French Irish Scottish German English

88 yr

61 yr 63 yr

4 polyps

50 yrs 38 yr

35 yrDx 38

8 yr10 yr

CRC Dx 48

Dx 50

KEYKEY

Endometrial CA

Colorectal CA

Adenomatous Polyps

Case 1 AssessmentCase 1 Assessment Joan meets Amsterdam II Criteria and is at risk for HNPCC

Refer to genetics for cancer genetic counseling and discussion of genetic testing for HNPCC

Testing options

1 Direct gene testing of MLH1 and MSH2 OR

2 MSIIHC screening of tumor tissue with gene sequencing if MSI positive

Case 2 TedCase 2 Ted Ted is 30 and wants a colonoscopy because his mother

was just diagnosed with colon cancer after routine screening at age 54 Family history reveals

1 Paternal grandfather died of CRC at age 79

2 No hx of endometrial ovarian small bowel or ureterkidney cancer on either side of family

3 Two maternal aunts cervical cancer at ages 30 amp 34

4 Maternal grandmother breast cancer age 85

Pedigree Case 2Pedigree Case 2Italian Irish German

KEY

CRC

Breast CA

Cervical CA

84

d 58 MIBrCa 85 yrs

d87

55 58 60

Colon CA 54 yrs

Cervical CA 30 yrs

Cervical CA 32 yrs

34 yrs 30 yrs

CRC 79 d82

56

Case 2 TedCase 2 Ted Verify Diagnoses Obtain and review pathology reports on

all reported cancers whenever possible

If diagnoses are correct Ted has no family history indicative of a known colon cancer syndrome (HNPCC FAP other)

Tedrsquos lifetime risk of colorectal CA is increased 2 to 3 fold due to one affected first degree relative (gt50)

Moderatefamilial risk Screening by colonoscopy starting at age 40 or 10 yrs earlier than earliest case in family is reasonable

Chemo PreventionChemo Prevention Evidence that ASA NSAIDs Calcium and COX-2

inhibitors may reduce incidence of CA by reducing ofadenomas

1048707 40-50 risk reduction for developing colorectal CA regardless of location in colon age gender and race

Generally performed by RCTrsquos in patients with priorcolorectal CA followed for recurrence of adenomas

Diet fiber and antioxidant vitamins have not beenshown by RCTrsquos to decrease risk of recurrent adenomas

COX-2irsquos and Sulindac have been shown to reduce thenumber of adenomas found in FAP alone

1048707 Not effective for sporadic colon CA 1048707 Actually can cause regression of adenomas

Characteristics of ldquoFamilialrdquo CRCCharacteristics of ldquoFamilialrdquo CRC

ldquoClusteringrdquo of colon cancer cases in the family (gt50 at diagnosis) without clear dominant pattern or

One close relative with CRC lt60 years and family history does not meet criteria for known hereditary CRC syndromes

Likely to be multiple low penetrant genes plus environmental factors at play

Family members warrant earlier CRC screening Starting at 40 years or 5-10 years earlier than age of diagnosis

of the youngest affected relative

Characteristics of Hereditary Characteristics of Hereditary CRCCRC

Multiple relatives with colorectal cancer One or more diagnosed at an early age (lt50)

Sequential generations affected Except in autosomal recessive syndromes

Other cancers in the family known to be associated with CRC (uterine ovarian GI)

Multiple primary tumors or polyps

Hereditary CRC SyndromesHereditary CRC Syndromes Hereditary Non-Polyposis Colorectal Cancer (HNPCC)

Variants Muir-Torre Turcot Familial Adenomatous Polyposis (FAP)

Variants Gardner Turcot Attenuated FAP APC mutation in Ashkenazi Jews

Others Multiple adenomatous polyposis syndromeMYH gene (MAP) Peutz-Jeghers syndrome (PJS) Familial Juvenile Polyposis (FJP)

HNPCC AKA ldquoLynch SyndromerdquoHNPCC AKA ldquoLynch Syndromerdquo

2-3 of all colorectal cancer cases Autosomal dominant high penetrance Typical age of CA onset is 40-50 years Multiple affected generations 60-70 right-sidedproximal CRC tumors Polyps may be present multiple primaries

common Can overlap with AFAP

HNPCCHNPCCbull Lifetime cancer risks

ndash Colorectal 80

ndash Endometrial 20-60

ndash Gastric 13-19

ndash Ovarian 9-12

ndash Biliary Tract 2

ndash Urinary Tract 4

ndash Small Bowel 1-4

ndash BrainCNS 1-3

HNPCCHNPCCClinical Diagnostic CriteriaClinical Diagnostic Criteria

Amsterdam II Criteria (3-2-1) 3 or more relatives with an HNPCC-related cancer

one of whom is a 1st degree relative of the other two 2 or more successive generations affected

1 or more cancers diagnosed before age 50

HNPCCHNPCC Caused by mutations or deletions in mismatched

repair (MMR) genes MSH2 MLH1 MSH6 (PMS2)

50 of families meeting Amsterdam II Criteria have detectable mutations

TestingScreening options Direct genetic testing of MMR genes (in select families) Initial screening of the tumor tissue by MSIIHC

MSIIHC ScreeningMSIIHC Screening Microsatellite Instability (MSI) on tumor tissue

can be used to screen for HNPCC in select cases

Immunohistochemistry (IHC) on tumor tissue

can be used to detect the presence or absence of the mismatch repair proteins (MSH2 MLH1 etc)

ldquoScreen positiverdquo individuals can be offered cancer genetic counselingassessment and targeted genetic testing

FAPFAP 1 in 10000 incidence 100rsquos to 1000rsquos of colonic adenomas by teens

Cancer risk colon gastric duodenum (periampulla) small bowel pancreas papillary thyroid childhood hepatoblastoma

7 risk of CRC by 21 yrs 93 by 50 yrs Autosomal dominant APC gene mutations Variants Gardner Turcot

FAP - SurveillanceFAP - Surveillance Colon

Annual sigmoidoscopy age 10-12 yrs Prophylactic colectomy following polyp detection with

continued surveillance of rectum ileal pouch Duodenalgastric

EGD age 25 repeat 1-3 yrs Thyroid

Annual PE age 10 Hepatoblastoma

Annual screen by abd US amp AFP from birth to 5 yrs

Attenuated FAPAttenuated FAP 20 to 100 polyps usually more proximal

Onset later than FAP average AOO = 50 Lifetime risk of CRC = 80

Extracolonic tumors occur at same rate as FAP Variant of FAP mutations in same APC gene Surveillance

annual colonoscopy starting late teens or early 20rsquos Option of subtotal colectomy

Genetic Testing FAPAFAPGenetic Testing FAPAFAP Test an affected family member first

After genetic counseling and informed consent

APC gene testing can confirm a suspected diagnosis

Family members of a person with a known APC mutation can have mutation-specific testing

Genetic testing for children at risk for FAP can be considered before beginning colon screening

APC gene mutation inAPC gene mutation inAshkenazi JewsAshkenazi Jews

Missense mutation (I1307K) associated with increased risk of CRC and adenomas in Ashkenazi Jews (AJ)

Found in 6 of the general AJ population

12 of AJs with CRC

29 of AJs with CRC and a positive family history

Lifetime risk of CRC in mutation carrier is 10-20

Screening colonoscopy every 2-5 yrs starting at 35 yrs

MAP syndromeMYH geneMAP syndromeMYH gene Multiple adenomatous polyposis (MAP) syndrome

Autosomal recessive mutations in the MYH gene Median number of polyps = 55 Mean age of polyp diagnosis = 30-50 years Polyps mainly small mildly dysplastic tubular adenomas Some

tubulovillous hyperplastic serrated adenomas microadenomas

30 of individuals with 15-100 polyps have homozygous mutations in the MYH gene

Genetic testing should be offered if gt15 polyps (and APC gene testing negative)

Peutz-Jeghers SyndromePeutz-Jeghers Syndrome lt1 of all CRC cases Hamartomatous polyps of GI tract as early as 1st decade Mucocutaneous hyper pigmentation

lips mouth buccal mucosa fingers Usually seen in children lt 5 yrs

Cancer risk colon small intestine stomach pancreas breast ovaries uterus testes

lungs kidneys Mutations in STK11 gene

found in 70 of familial cases and 30-70 of sporadic cases

Familial Juvenile PolyposisFamilial Juvenile Polyposis

lt1 of all CRC cases

Autosomal dominant

5 or more juvenile polyps in colon or GI tract

Appear in 1st or 2nd decade

50 lifetime risk of CRC AOO in 30rsquos

Increased risk gastric GI pancreatic CA

~50 of cases have mutations in either the MADH4 or BMPR1A genes

Family Health HistoryFamily Health History

ldquoThe family tree has become the most important genetic test of all The more you know the more tools you have to practice preventive medicinerdquo

Donna Russo Certified Genetic Counselor NY Presbyterian-Columbia Hospital

Goal ClassificationGoal ClassificationAssessment Risk Classification Intervention

Family History

Average

Moderate

(ldquoFamilialrdquo)

HighGenetic

Personalized prevention recommendations

Standard prevention recommendations

Referral for genetic evaluation with personalized prevention recommendations

Consider Genetics Referral forConsider Genetics Referral for

Two or more family members with CRC at least one lt50

Three or more family members wCRC any age

Patient with colon cancer before 40 yrs

Endometrial cancer and family history of CRC lt50

Persons with more than one primary CRC lt50 yrs or with both endometrial CA and CRC

Family or personal history of CRC and one or more 1st degree relative with an HNPCC-related cancer one diagnosed lt50 yrs

Same side of family

Consider Genetics Referral forConsider Genetics Referral for

MSI andor IHC tumor results suspicious for HNPCC

Autosomal dominant pattern of cancers in the family

Persons with 15 or more adenomatous colorectal polyps

Persons with multiple hamartomatous or juvenile GI polyps

Persons with a family history of a known hereditary cancer syndrome

CRC Risk ManagementCRC Risk Management

Average Risk

1 No family history CRC OR2 One 2nd or 3rd degree relative with CRC

FOBT annually + flex sig every 5 years OR Colonoscopy every 10 years OR DCBE every 5 years

Age to Begin50 years

CRC Risk ManagementCRC Risk ManagementModerateFamily history Two 1st degree relatives with CRC any age

or one 1st degree relative with CRC lt 60- Colonoscopy every 5 yrs

One 1st degree relative with CRC gt60 or two 2nd degree relatives with CRC any age- Average risk screening

Or 5-10 yrs earlier than earliest case in family

Age to begin

40 years

40 years

CRC Risk ManagementCRC Risk Management

Age to Begin

HNPCC or suspected HNPCC 20-25 years 1 Colonoscopy every 1-2 yrs

2 Genetic counseling consider genetic testing

FAP or suspected FAP 10-12 years 1 Flex sig or colonoscopy every1-2 yrs

2 Genetic counseling consider genetic testing

Case 1 JoanCase 1 Joan Joan age 38 was recently diagnosed with

endometrial cancer Family history reveals

1 Paternal grandmother endometrial cancer age 50 2 Paternal uncle colon cancer age 48 3 Father colonoscopy at age 50 four adenomatous

polyps removed 4 No other significant history 5 Both sides of the family are Northern European

Caucasian

Pedigree Case 1Pedigree Case 1French Irish Scottish German English

88 yr

61 yr 63 yr

4 polyps

50 yrs 38 yr

35 yrDx 38

8 yr10 yr

CRC Dx 48

Dx 50

KEYKEY

Endometrial CA

Colorectal CA

Adenomatous Polyps

Case 1 AssessmentCase 1 Assessment Joan meets Amsterdam II Criteria and is at risk for HNPCC

Refer to genetics for cancer genetic counseling and discussion of genetic testing for HNPCC

Testing options

1 Direct gene testing of MLH1 and MSH2 OR

2 MSIIHC screening of tumor tissue with gene sequencing if MSI positive

Case 2 TedCase 2 Ted Ted is 30 and wants a colonoscopy because his mother

was just diagnosed with colon cancer after routine screening at age 54 Family history reveals

1 Paternal grandfather died of CRC at age 79

2 No hx of endometrial ovarian small bowel or ureterkidney cancer on either side of family

3 Two maternal aunts cervical cancer at ages 30 amp 34

4 Maternal grandmother breast cancer age 85

Pedigree Case 2Pedigree Case 2Italian Irish German

KEY

CRC

Breast CA

Cervical CA

84

d 58 MIBrCa 85 yrs

d87

55 58 60

Colon CA 54 yrs

Cervical CA 30 yrs

Cervical CA 32 yrs

34 yrs 30 yrs

CRC 79 d82

56

Case 2 TedCase 2 Ted Verify Diagnoses Obtain and review pathology reports on

all reported cancers whenever possible

If diagnoses are correct Ted has no family history indicative of a known colon cancer syndrome (HNPCC FAP other)

Tedrsquos lifetime risk of colorectal CA is increased 2 to 3 fold due to one affected first degree relative (gt50)

Moderatefamilial risk Screening by colonoscopy starting at age 40 or 10 yrs earlier than earliest case in family is reasonable

Chemo PreventionChemo Prevention Evidence that ASA NSAIDs Calcium and COX-2

inhibitors may reduce incidence of CA by reducing ofadenomas

1048707 40-50 risk reduction for developing colorectal CA regardless of location in colon age gender and race

Generally performed by RCTrsquos in patients with priorcolorectal CA followed for recurrence of adenomas

Diet fiber and antioxidant vitamins have not beenshown by RCTrsquos to decrease risk of recurrent adenomas

COX-2irsquos and Sulindac have been shown to reduce thenumber of adenomas found in FAP alone

1048707 Not effective for sporadic colon CA 1048707 Actually can cause regression of adenomas

Characteristics of Hereditary Characteristics of Hereditary CRCCRC

Multiple relatives with colorectal cancer One or more diagnosed at an early age (lt50)

Sequential generations affected Except in autosomal recessive syndromes

Other cancers in the family known to be associated with CRC (uterine ovarian GI)

Multiple primary tumors or polyps

Hereditary CRC SyndromesHereditary CRC Syndromes Hereditary Non-Polyposis Colorectal Cancer (HNPCC)

Variants Muir-Torre Turcot Familial Adenomatous Polyposis (FAP)

Variants Gardner Turcot Attenuated FAP APC mutation in Ashkenazi Jews

Others Multiple adenomatous polyposis syndromeMYH gene (MAP) Peutz-Jeghers syndrome (PJS) Familial Juvenile Polyposis (FJP)

HNPCC AKA ldquoLynch SyndromerdquoHNPCC AKA ldquoLynch Syndromerdquo

2-3 of all colorectal cancer cases Autosomal dominant high penetrance Typical age of CA onset is 40-50 years Multiple affected generations 60-70 right-sidedproximal CRC tumors Polyps may be present multiple primaries

common Can overlap with AFAP

HNPCCHNPCCbull Lifetime cancer risks

ndash Colorectal 80

ndash Endometrial 20-60

ndash Gastric 13-19

ndash Ovarian 9-12

ndash Biliary Tract 2

ndash Urinary Tract 4

ndash Small Bowel 1-4

ndash BrainCNS 1-3

HNPCCHNPCCClinical Diagnostic CriteriaClinical Diagnostic Criteria

Amsterdam II Criteria (3-2-1) 3 or more relatives with an HNPCC-related cancer

one of whom is a 1st degree relative of the other two 2 or more successive generations affected

1 or more cancers diagnosed before age 50

HNPCCHNPCC Caused by mutations or deletions in mismatched

repair (MMR) genes MSH2 MLH1 MSH6 (PMS2)

50 of families meeting Amsterdam II Criteria have detectable mutations

TestingScreening options Direct genetic testing of MMR genes (in select families) Initial screening of the tumor tissue by MSIIHC

MSIIHC ScreeningMSIIHC Screening Microsatellite Instability (MSI) on tumor tissue

can be used to screen for HNPCC in select cases

Immunohistochemistry (IHC) on tumor tissue

can be used to detect the presence or absence of the mismatch repair proteins (MSH2 MLH1 etc)

ldquoScreen positiverdquo individuals can be offered cancer genetic counselingassessment and targeted genetic testing

FAPFAP 1 in 10000 incidence 100rsquos to 1000rsquos of colonic adenomas by teens

Cancer risk colon gastric duodenum (periampulla) small bowel pancreas papillary thyroid childhood hepatoblastoma

7 risk of CRC by 21 yrs 93 by 50 yrs Autosomal dominant APC gene mutations Variants Gardner Turcot

FAP - SurveillanceFAP - Surveillance Colon

Annual sigmoidoscopy age 10-12 yrs Prophylactic colectomy following polyp detection with

continued surveillance of rectum ileal pouch Duodenalgastric

EGD age 25 repeat 1-3 yrs Thyroid

Annual PE age 10 Hepatoblastoma

Annual screen by abd US amp AFP from birth to 5 yrs

Attenuated FAPAttenuated FAP 20 to 100 polyps usually more proximal

Onset later than FAP average AOO = 50 Lifetime risk of CRC = 80

Extracolonic tumors occur at same rate as FAP Variant of FAP mutations in same APC gene Surveillance

annual colonoscopy starting late teens or early 20rsquos Option of subtotal colectomy

Genetic Testing FAPAFAPGenetic Testing FAPAFAP Test an affected family member first

After genetic counseling and informed consent

APC gene testing can confirm a suspected diagnosis

Family members of a person with a known APC mutation can have mutation-specific testing

Genetic testing for children at risk for FAP can be considered before beginning colon screening

APC gene mutation inAPC gene mutation inAshkenazi JewsAshkenazi Jews

Missense mutation (I1307K) associated with increased risk of CRC and adenomas in Ashkenazi Jews (AJ)

Found in 6 of the general AJ population

12 of AJs with CRC

29 of AJs with CRC and a positive family history

Lifetime risk of CRC in mutation carrier is 10-20

Screening colonoscopy every 2-5 yrs starting at 35 yrs

MAP syndromeMYH geneMAP syndromeMYH gene Multiple adenomatous polyposis (MAP) syndrome

Autosomal recessive mutations in the MYH gene Median number of polyps = 55 Mean age of polyp diagnosis = 30-50 years Polyps mainly small mildly dysplastic tubular adenomas Some

tubulovillous hyperplastic serrated adenomas microadenomas

30 of individuals with 15-100 polyps have homozygous mutations in the MYH gene

Genetic testing should be offered if gt15 polyps (and APC gene testing negative)

Peutz-Jeghers SyndromePeutz-Jeghers Syndrome lt1 of all CRC cases Hamartomatous polyps of GI tract as early as 1st decade Mucocutaneous hyper pigmentation

lips mouth buccal mucosa fingers Usually seen in children lt 5 yrs

Cancer risk colon small intestine stomach pancreas breast ovaries uterus testes

lungs kidneys Mutations in STK11 gene

found in 70 of familial cases and 30-70 of sporadic cases

Familial Juvenile PolyposisFamilial Juvenile Polyposis

lt1 of all CRC cases

Autosomal dominant

5 or more juvenile polyps in colon or GI tract

Appear in 1st or 2nd decade

50 lifetime risk of CRC AOO in 30rsquos

Increased risk gastric GI pancreatic CA

~50 of cases have mutations in either the MADH4 or BMPR1A genes

Family Health HistoryFamily Health History

ldquoThe family tree has become the most important genetic test of all The more you know the more tools you have to practice preventive medicinerdquo

Donna Russo Certified Genetic Counselor NY Presbyterian-Columbia Hospital

Goal ClassificationGoal ClassificationAssessment Risk Classification Intervention

Family History

Average

Moderate

(ldquoFamilialrdquo)

HighGenetic

Personalized prevention recommendations

Standard prevention recommendations

Referral for genetic evaluation with personalized prevention recommendations

Consider Genetics Referral forConsider Genetics Referral for

Two or more family members with CRC at least one lt50

Three or more family members wCRC any age

Patient with colon cancer before 40 yrs

Endometrial cancer and family history of CRC lt50

Persons with more than one primary CRC lt50 yrs or with both endometrial CA and CRC

Family or personal history of CRC and one or more 1st degree relative with an HNPCC-related cancer one diagnosed lt50 yrs

Same side of family

Consider Genetics Referral forConsider Genetics Referral for

MSI andor IHC tumor results suspicious for HNPCC

Autosomal dominant pattern of cancers in the family

Persons with 15 or more adenomatous colorectal polyps

Persons with multiple hamartomatous or juvenile GI polyps

Persons with a family history of a known hereditary cancer syndrome

CRC Risk ManagementCRC Risk Management

Average Risk

1 No family history CRC OR2 One 2nd or 3rd degree relative with CRC

FOBT annually + flex sig every 5 years OR Colonoscopy every 10 years OR DCBE every 5 years

Age to Begin50 years

CRC Risk ManagementCRC Risk ManagementModerateFamily history Two 1st degree relatives with CRC any age

or one 1st degree relative with CRC lt 60- Colonoscopy every 5 yrs

One 1st degree relative with CRC gt60 or two 2nd degree relatives with CRC any age- Average risk screening

Or 5-10 yrs earlier than earliest case in family

Age to begin

40 years

40 years

CRC Risk ManagementCRC Risk Management

Age to Begin

HNPCC or suspected HNPCC 20-25 years 1 Colonoscopy every 1-2 yrs

2 Genetic counseling consider genetic testing

FAP or suspected FAP 10-12 years 1 Flex sig or colonoscopy every1-2 yrs

2 Genetic counseling consider genetic testing

Case 1 JoanCase 1 Joan Joan age 38 was recently diagnosed with

endometrial cancer Family history reveals

1 Paternal grandmother endometrial cancer age 50 2 Paternal uncle colon cancer age 48 3 Father colonoscopy at age 50 four adenomatous

polyps removed 4 No other significant history 5 Both sides of the family are Northern European

Caucasian

Pedigree Case 1Pedigree Case 1French Irish Scottish German English

88 yr

61 yr 63 yr

4 polyps

50 yrs 38 yr

35 yrDx 38

8 yr10 yr

CRC Dx 48

Dx 50

KEYKEY

Endometrial CA

Colorectal CA

Adenomatous Polyps

Case 1 AssessmentCase 1 Assessment Joan meets Amsterdam II Criteria and is at risk for HNPCC

Refer to genetics for cancer genetic counseling and discussion of genetic testing for HNPCC

Testing options

1 Direct gene testing of MLH1 and MSH2 OR

2 MSIIHC screening of tumor tissue with gene sequencing if MSI positive

Case 2 TedCase 2 Ted Ted is 30 and wants a colonoscopy because his mother

was just diagnosed with colon cancer after routine screening at age 54 Family history reveals

1 Paternal grandfather died of CRC at age 79

2 No hx of endometrial ovarian small bowel or ureterkidney cancer on either side of family

3 Two maternal aunts cervical cancer at ages 30 amp 34

4 Maternal grandmother breast cancer age 85

Pedigree Case 2Pedigree Case 2Italian Irish German

KEY

CRC

Breast CA

Cervical CA

84

d 58 MIBrCa 85 yrs

d87

55 58 60

Colon CA 54 yrs

Cervical CA 30 yrs

Cervical CA 32 yrs

34 yrs 30 yrs

CRC 79 d82

56

Case 2 TedCase 2 Ted Verify Diagnoses Obtain and review pathology reports on

all reported cancers whenever possible

If diagnoses are correct Ted has no family history indicative of a known colon cancer syndrome (HNPCC FAP other)

Tedrsquos lifetime risk of colorectal CA is increased 2 to 3 fold due to one affected first degree relative (gt50)

Moderatefamilial risk Screening by colonoscopy starting at age 40 or 10 yrs earlier than earliest case in family is reasonable

Chemo PreventionChemo Prevention Evidence that ASA NSAIDs Calcium and COX-2

inhibitors may reduce incidence of CA by reducing ofadenomas

1048707 40-50 risk reduction for developing colorectal CA regardless of location in colon age gender and race

Generally performed by RCTrsquos in patients with priorcolorectal CA followed for recurrence of adenomas

Diet fiber and antioxidant vitamins have not beenshown by RCTrsquos to decrease risk of recurrent adenomas

COX-2irsquos and Sulindac have been shown to reduce thenumber of adenomas found in FAP alone

1048707 Not effective for sporadic colon CA 1048707 Actually can cause regression of adenomas

Hereditary CRC SyndromesHereditary CRC Syndromes Hereditary Non-Polyposis Colorectal Cancer (HNPCC)

Variants Muir-Torre Turcot Familial Adenomatous Polyposis (FAP)

Variants Gardner Turcot Attenuated FAP APC mutation in Ashkenazi Jews

Others Multiple adenomatous polyposis syndromeMYH gene (MAP) Peutz-Jeghers syndrome (PJS) Familial Juvenile Polyposis (FJP)

HNPCC AKA ldquoLynch SyndromerdquoHNPCC AKA ldquoLynch Syndromerdquo

2-3 of all colorectal cancer cases Autosomal dominant high penetrance Typical age of CA onset is 40-50 years Multiple affected generations 60-70 right-sidedproximal CRC tumors Polyps may be present multiple primaries

common Can overlap with AFAP

HNPCCHNPCCbull Lifetime cancer risks

ndash Colorectal 80

ndash Endometrial 20-60

ndash Gastric 13-19

ndash Ovarian 9-12

ndash Biliary Tract 2

ndash Urinary Tract 4

ndash Small Bowel 1-4

ndash BrainCNS 1-3

HNPCCHNPCCClinical Diagnostic CriteriaClinical Diagnostic Criteria

Amsterdam II Criteria (3-2-1) 3 or more relatives with an HNPCC-related cancer

one of whom is a 1st degree relative of the other two 2 or more successive generations affected

1 or more cancers diagnosed before age 50

HNPCCHNPCC Caused by mutations or deletions in mismatched

repair (MMR) genes MSH2 MLH1 MSH6 (PMS2)

50 of families meeting Amsterdam II Criteria have detectable mutations

TestingScreening options Direct genetic testing of MMR genes (in select families) Initial screening of the tumor tissue by MSIIHC

MSIIHC ScreeningMSIIHC Screening Microsatellite Instability (MSI) on tumor tissue

can be used to screen for HNPCC in select cases

Immunohistochemistry (IHC) on tumor tissue

can be used to detect the presence or absence of the mismatch repair proteins (MSH2 MLH1 etc)

ldquoScreen positiverdquo individuals can be offered cancer genetic counselingassessment and targeted genetic testing

FAPFAP 1 in 10000 incidence 100rsquos to 1000rsquos of colonic adenomas by teens

Cancer risk colon gastric duodenum (periampulla) small bowel pancreas papillary thyroid childhood hepatoblastoma

7 risk of CRC by 21 yrs 93 by 50 yrs Autosomal dominant APC gene mutations Variants Gardner Turcot

FAP - SurveillanceFAP - Surveillance Colon

Annual sigmoidoscopy age 10-12 yrs Prophylactic colectomy following polyp detection with

continued surveillance of rectum ileal pouch Duodenalgastric

EGD age 25 repeat 1-3 yrs Thyroid

Annual PE age 10 Hepatoblastoma

Annual screen by abd US amp AFP from birth to 5 yrs

Attenuated FAPAttenuated FAP 20 to 100 polyps usually more proximal

Onset later than FAP average AOO = 50 Lifetime risk of CRC = 80

Extracolonic tumors occur at same rate as FAP Variant of FAP mutations in same APC gene Surveillance

annual colonoscopy starting late teens or early 20rsquos Option of subtotal colectomy

Genetic Testing FAPAFAPGenetic Testing FAPAFAP Test an affected family member first

After genetic counseling and informed consent

APC gene testing can confirm a suspected diagnosis

Family members of a person with a known APC mutation can have mutation-specific testing

Genetic testing for children at risk for FAP can be considered before beginning colon screening

APC gene mutation inAPC gene mutation inAshkenazi JewsAshkenazi Jews

Missense mutation (I1307K) associated with increased risk of CRC and adenomas in Ashkenazi Jews (AJ)

Found in 6 of the general AJ population

12 of AJs with CRC

29 of AJs with CRC and a positive family history

Lifetime risk of CRC in mutation carrier is 10-20

Screening colonoscopy every 2-5 yrs starting at 35 yrs

MAP syndromeMYH geneMAP syndromeMYH gene Multiple adenomatous polyposis (MAP) syndrome

Autosomal recessive mutations in the MYH gene Median number of polyps = 55 Mean age of polyp diagnosis = 30-50 years Polyps mainly small mildly dysplastic tubular adenomas Some

tubulovillous hyperplastic serrated adenomas microadenomas

30 of individuals with 15-100 polyps have homozygous mutations in the MYH gene

Genetic testing should be offered if gt15 polyps (and APC gene testing negative)

Peutz-Jeghers SyndromePeutz-Jeghers Syndrome lt1 of all CRC cases Hamartomatous polyps of GI tract as early as 1st decade Mucocutaneous hyper pigmentation

lips mouth buccal mucosa fingers Usually seen in children lt 5 yrs

Cancer risk colon small intestine stomach pancreas breast ovaries uterus testes

lungs kidneys Mutations in STK11 gene

found in 70 of familial cases and 30-70 of sporadic cases

Familial Juvenile PolyposisFamilial Juvenile Polyposis

lt1 of all CRC cases

Autosomal dominant

5 or more juvenile polyps in colon or GI tract

Appear in 1st or 2nd decade

50 lifetime risk of CRC AOO in 30rsquos

Increased risk gastric GI pancreatic CA

~50 of cases have mutations in either the MADH4 or BMPR1A genes

Family Health HistoryFamily Health History

ldquoThe family tree has become the most important genetic test of all The more you know the more tools you have to practice preventive medicinerdquo

Donna Russo Certified Genetic Counselor NY Presbyterian-Columbia Hospital

Goal ClassificationGoal ClassificationAssessment Risk Classification Intervention

Family History

Average

Moderate

(ldquoFamilialrdquo)

HighGenetic

Personalized prevention recommendations

Standard prevention recommendations

Referral for genetic evaluation with personalized prevention recommendations

Consider Genetics Referral forConsider Genetics Referral for

Two or more family members with CRC at least one lt50

Three or more family members wCRC any age

Patient with colon cancer before 40 yrs

Endometrial cancer and family history of CRC lt50

Persons with more than one primary CRC lt50 yrs or with both endometrial CA and CRC

Family or personal history of CRC and one or more 1st degree relative with an HNPCC-related cancer one diagnosed lt50 yrs

Same side of family

Consider Genetics Referral forConsider Genetics Referral for

MSI andor IHC tumor results suspicious for HNPCC

Autosomal dominant pattern of cancers in the family

Persons with 15 or more adenomatous colorectal polyps

Persons with multiple hamartomatous or juvenile GI polyps

Persons with a family history of a known hereditary cancer syndrome

CRC Risk ManagementCRC Risk Management

Average Risk

1 No family history CRC OR2 One 2nd or 3rd degree relative with CRC

FOBT annually + flex sig every 5 years OR Colonoscopy every 10 years OR DCBE every 5 years

Age to Begin50 years

CRC Risk ManagementCRC Risk ManagementModerateFamily history Two 1st degree relatives with CRC any age

or one 1st degree relative with CRC lt 60- Colonoscopy every 5 yrs

One 1st degree relative with CRC gt60 or two 2nd degree relatives with CRC any age- Average risk screening

Or 5-10 yrs earlier than earliest case in family

Age to begin

40 years

40 years

CRC Risk ManagementCRC Risk Management

Age to Begin

HNPCC or suspected HNPCC 20-25 years 1 Colonoscopy every 1-2 yrs

2 Genetic counseling consider genetic testing

FAP or suspected FAP 10-12 years 1 Flex sig or colonoscopy every1-2 yrs

2 Genetic counseling consider genetic testing

Case 1 JoanCase 1 Joan Joan age 38 was recently diagnosed with

endometrial cancer Family history reveals

1 Paternal grandmother endometrial cancer age 50 2 Paternal uncle colon cancer age 48 3 Father colonoscopy at age 50 four adenomatous

polyps removed 4 No other significant history 5 Both sides of the family are Northern European

Caucasian

Pedigree Case 1Pedigree Case 1French Irish Scottish German English

88 yr

61 yr 63 yr

4 polyps

50 yrs 38 yr

35 yrDx 38

8 yr10 yr

CRC Dx 48

Dx 50

KEYKEY

Endometrial CA

Colorectal CA

Adenomatous Polyps

Case 1 AssessmentCase 1 Assessment Joan meets Amsterdam II Criteria and is at risk for HNPCC

Refer to genetics for cancer genetic counseling and discussion of genetic testing for HNPCC

Testing options

1 Direct gene testing of MLH1 and MSH2 OR

2 MSIIHC screening of tumor tissue with gene sequencing if MSI positive

Case 2 TedCase 2 Ted Ted is 30 and wants a colonoscopy because his mother

was just diagnosed with colon cancer after routine screening at age 54 Family history reveals

1 Paternal grandfather died of CRC at age 79

2 No hx of endometrial ovarian small bowel or ureterkidney cancer on either side of family

3 Two maternal aunts cervical cancer at ages 30 amp 34

4 Maternal grandmother breast cancer age 85

Pedigree Case 2Pedigree Case 2Italian Irish German

KEY

CRC

Breast CA

Cervical CA

84

d 58 MIBrCa 85 yrs

d87

55 58 60

Colon CA 54 yrs

Cervical CA 30 yrs

Cervical CA 32 yrs

34 yrs 30 yrs

CRC 79 d82

56

Case 2 TedCase 2 Ted Verify Diagnoses Obtain and review pathology reports on

all reported cancers whenever possible

If diagnoses are correct Ted has no family history indicative of a known colon cancer syndrome (HNPCC FAP other)

Tedrsquos lifetime risk of colorectal CA is increased 2 to 3 fold due to one affected first degree relative (gt50)

Moderatefamilial risk Screening by colonoscopy starting at age 40 or 10 yrs earlier than earliest case in family is reasonable

Chemo PreventionChemo Prevention Evidence that ASA NSAIDs Calcium and COX-2

inhibitors may reduce incidence of CA by reducing ofadenomas

1048707 40-50 risk reduction for developing colorectal CA regardless of location in colon age gender and race

Generally performed by RCTrsquos in patients with priorcolorectal CA followed for recurrence of adenomas

Diet fiber and antioxidant vitamins have not beenshown by RCTrsquos to decrease risk of recurrent adenomas

COX-2irsquos and Sulindac have been shown to reduce thenumber of adenomas found in FAP alone

1048707 Not effective for sporadic colon CA 1048707 Actually can cause regression of adenomas

HNPCC AKA ldquoLynch SyndromerdquoHNPCC AKA ldquoLynch Syndromerdquo

2-3 of all colorectal cancer cases Autosomal dominant high penetrance Typical age of CA onset is 40-50 years Multiple affected generations 60-70 right-sidedproximal CRC tumors Polyps may be present multiple primaries

common Can overlap with AFAP

HNPCCHNPCCbull Lifetime cancer risks

ndash Colorectal 80

ndash Endometrial 20-60

ndash Gastric 13-19

ndash Ovarian 9-12

ndash Biliary Tract 2

ndash Urinary Tract 4

ndash Small Bowel 1-4

ndash BrainCNS 1-3

HNPCCHNPCCClinical Diagnostic CriteriaClinical Diagnostic Criteria

Amsterdam II Criteria (3-2-1) 3 or more relatives with an HNPCC-related cancer

one of whom is a 1st degree relative of the other two 2 or more successive generations affected

1 or more cancers diagnosed before age 50

HNPCCHNPCC Caused by mutations or deletions in mismatched

repair (MMR) genes MSH2 MLH1 MSH6 (PMS2)

50 of families meeting Amsterdam II Criteria have detectable mutations

TestingScreening options Direct genetic testing of MMR genes (in select families) Initial screening of the tumor tissue by MSIIHC

MSIIHC ScreeningMSIIHC Screening Microsatellite Instability (MSI) on tumor tissue

can be used to screen for HNPCC in select cases

Immunohistochemistry (IHC) on tumor tissue

can be used to detect the presence or absence of the mismatch repair proteins (MSH2 MLH1 etc)

ldquoScreen positiverdquo individuals can be offered cancer genetic counselingassessment and targeted genetic testing

FAPFAP 1 in 10000 incidence 100rsquos to 1000rsquos of colonic adenomas by teens

Cancer risk colon gastric duodenum (periampulla) small bowel pancreas papillary thyroid childhood hepatoblastoma

7 risk of CRC by 21 yrs 93 by 50 yrs Autosomal dominant APC gene mutations Variants Gardner Turcot

FAP - SurveillanceFAP - Surveillance Colon

Annual sigmoidoscopy age 10-12 yrs Prophylactic colectomy following polyp detection with

continued surveillance of rectum ileal pouch Duodenalgastric

EGD age 25 repeat 1-3 yrs Thyroid

Annual PE age 10 Hepatoblastoma

Annual screen by abd US amp AFP from birth to 5 yrs

Attenuated FAPAttenuated FAP 20 to 100 polyps usually more proximal

Onset later than FAP average AOO = 50 Lifetime risk of CRC = 80

Extracolonic tumors occur at same rate as FAP Variant of FAP mutations in same APC gene Surveillance

annual colonoscopy starting late teens or early 20rsquos Option of subtotal colectomy

Genetic Testing FAPAFAPGenetic Testing FAPAFAP Test an affected family member first

After genetic counseling and informed consent

APC gene testing can confirm a suspected diagnosis

Family members of a person with a known APC mutation can have mutation-specific testing

Genetic testing for children at risk for FAP can be considered before beginning colon screening

APC gene mutation inAPC gene mutation inAshkenazi JewsAshkenazi Jews

Missense mutation (I1307K) associated with increased risk of CRC and adenomas in Ashkenazi Jews (AJ)

Found in 6 of the general AJ population

12 of AJs with CRC

29 of AJs with CRC and a positive family history

Lifetime risk of CRC in mutation carrier is 10-20

Screening colonoscopy every 2-5 yrs starting at 35 yrs

MAP syndromeMYH geneMAP syndromeMYH gene Multiple adenomatous polyposis (MAP) syndrome

Autosomal recessive mutations in the MYH gene Median number of polyps = 55 Mean age of polyp diagnosis = 30-50 years Polyps mainly small mildly dysplastic tubular adenomas Some

tubulovillous hyperplastic serrated adenomas microadenomas

30 of individuals with 15-100 polyps have homozygous mutations in the MYH gene

Genetic testing should be offered if gt15 polyps (and APC gene testing negative)

Peutz-Jeghers SyndromePeutz-Jeghers Syndrome lt1 of all CRC cases Hamartomatous polyps of GI tract as early as 1st decade Mucocutaneous hyper pigmentation

lips mouth buccal mucosa fingers Usually seen in children lt 5 yrs

Cancer risk colon small intestine stomach pancreas breast ovaries uterus testes

lungs kidneys Mutations in STK11 gene

found in 70 of familial cases and 30-70 of sporadic cases

Familial Juvenile PolyposisFamilial Juvenile Polyposis

lt1 of all CRC cases

Autosomal dominant

5 or more juvenile polyps in colon or GI tract

Appear in 1st or 2nd decade

50 lifetime risk of CRC AOO in 30rsquos

Increased risk gastric GI pancreatic CA

~50 of cases have mutations in either the MADH4 or BMPR1A genes

Family Health HistoryFamily Health History

ldquoThe family tree has become the most important genetic test of all The more you know the more tools you have to practice preventive medicinerdquo

Donna Russo Certified Genetic Counselor NY Presbyterian-Columbia Hospital

Goal ClassificationGoal ClassificationAssessment Risk Classification Intervention

Family History

Average

Moderate

(ldquoFamilialrdquo)

HighGenetic

Personalized prevention recommendations

Standard prevention recommendations

Referral for genetic evaluation with personalized prevention recommendations

Consider Genetics Referral forConsider Genetics Referral for

Two or more family members with CRC at least one lt50

Three or more family members wCRC any age

Patient with colon cancer before 40 yrs

Endometrial cancer and family history of CRC lt50

Persons with more than one primary CRC lt50 yrs or with both endometrial CA and CRC

Family or personal history of CRC and one or more 1st degree relative with an HNPCC-related cancer one diagnosed lt50 yrs

Same side of family

Consider Genetics Referral forConsider Genetics Referral for

MSI andor IHC tumor results suspicious for HNPCC

Autosomal dominant pattern of cancers in the family

Persons with 15 or more adenomatous colorectal polyps

Persons with multiple hamartomatous or juvenile GI polyps

Persons with a family history of a known hereditary cancer syndrome

CRC Risk ManagementCRC Risk Management

Average Risk

1 No family history CRC OR2 One 2nd or 3rd degree relative with CRC

FOBT annually + flex sig every 5 years OR Colonoscopy every 10 years OR DCBE every 5 years

Age to Begin50 years

CRC Risk ManagementCRC Risk ManagementModerateFamily history Two 1st degree relatives with CRC any age

or one 1st degree relative with CRC lt 60- Colonoscopy every 5 yrs

One 1st degree relative with CRC gt60 or two 2nd degree relatives with CRC any age- Average risk screening

Or 5-10 yrs earlier than earliest case in family

Age to begin

40 years

40 years

CRC Risk ManagementCRC Risk Management

Age to Begin

HNPCC or suspected HNPCC 20-25 years 1 Colonoscopy every 1-2 yrs

2 Genetic counseling consider genetic testing

FAP or suspected FAP 10-12 years 1 Flex sig or colonoscopy every1-2 yrs

2 Genetic counseling consider genetic testing

Case 1 JoanCase 1 Joan Joan age 38 was recently diagnosed with

endometrial cancer Family history reveals

1 Paternal grandmother endometrial cancer age 50 2 Paternal uncle colon cancer age 48 3 Father colonoscopy at age 50 four adenomatous

polyps removed 4 No other significant history 5 Both sides of the family are Northern European

Caucasian

Pedigree Case 1Pedigree Case 1French Irish Scottish German English

88 yr

61 yr 63 yr

4 polyps

50 yrs 38 yr

35 yrDx 38

8 yr10 yr

CRC Dx 48

Dx 50

KEYKEY

Endometrial CA

Colorectal CA

Adenomatous Polyps

Case 1 AssessmentCase 1 Assessment Joan meets Amsterdam II Criteria and is at risk for HNPCC

Refer to genetics for cancer genetic counseling and discussion of genetic testing for HNPCC

Testing options

1 Direct gene testing of MLH1 and MSH2 OR

2 MSIIHC screening of tumor tissue with gene sequencing if MSI positive

Case 2 TedCase 2 Ted Ted is 30 and wants a colonoscopy because his mother

was just diagnosed with colon cancer after routine screening at age 54 Family history reveals

1 Paternal grandfather died of CRC at age 79

2 No hx of endometrial ovarian small bowel or ureterkidney cancer on either side of family

3 Two maternal aunts cervical cancer at ages 30 amp 34

4 Maternal grandmother breast cancer age 85

Pedigree Case 2Pedigree Case 2Italian Irish German

KEY

CRC

Breast CA

Cervical CA

84

d 58 MIBrCa 85 yrs

d87

55 58 60

Colon CA 54 yrs

Cervical CA 30 yrs

Cervical CA 32 yrs

34 yrs 30 yrs

CRC 79 d82

56

Case 2 TedCase 2 Ted Verify Diagnoses Obtain and review pathology reports on

all reported cancers whenever possible

If diagnoses are correct Ted has no family history indicative of a known colon cancer syndrome (HNPCC FAP other)

Tedrsquos lifetime risk of colorectal CA is increased 2 to 3 fold due to one affected first degree relative (gt50)

Moderatefamilial risk Screening by colonoscopy starting at age 40 or 10 yrs earlier than earliest case in family is reasonable

Chemo PreventionChemo Prevention Evidence that ASA NSAIDs Calcium and COX-2

inhibitors may reduce incidence of CA by reducing ofadenomas

1048707 40-50 risk reduction for developing colorectal CA regardless of location in colon age gender and race

Generally performed by RCTrsquos in patients with priorcolorectal CA followed for recurrence of adenomas

Diet fiber and antioxidant vitamins have not beenshown by RCTrsquos to decrease risk of recurrent adenomas

COX-2irsquos and Sulindac have been shown to reduce thenumber of adenomas found in FAP alone

1048707 Not effective for sporadic colon CA 1048707 Actually can cause regression of adenomas

HNPCCHNPCCbull Lifetime cancer risks

ndash Colorectal 80

ndash Endometrial 20-60

ndash Gastric 13-19

ndash Ovarian 9-12

ndash Biliary Tract 2

ndash Urinary Tract 4

ndash Small Bowel 1-4

ndash BrainCNS 1-3

HNPCCHNPCCClinical Diagnostic CriteriaClinical Diagnostic Criteria

Amsterdam II Criteria (3-2-1) 3 or more relatives with an HNPCC-related cancer

one of whom is a 1st degree relative of the other two 2 or more successive generations affected

1 or more cancers diagnosed before age 50

HNPCCHNPCC Caused by mutations or deletions in mismatched

repair (MMR) genes MSH2 MLH1 MSH6 (PMS2)

50 of families meeting Amsterdam II Criteria have detectable mutations

TestingScreening options Direct genetic testing of MMR genes (in select families) Initial screening of the tumor tissue by MSIIHC

MSIIHC ScreeningMSIIHC Screening Microsatellite Instability (MSI) on tumor tissue

can be used to screen for HNPCC in select cases

Immunohistochemistry (IHC) on tumor tissue

can be used to detect the presence or absence of the mismatch repair proteins (MSH2 MLH1 etc)

ldquoScreen positiverdquo individuals can be offered cancer genetic counselingassessment and targeted genetic testing

FAPFAP 1 in 10000 incidence 100rsquos to 1000rsquos of colonic adenomas by teens

Cancer risk colon gastric duodenum (periampulla) small bowel pancreas papillary thyroid childhood hepatoblastoma

7 risk of CRC by 21 yrs 93 by 50 yrs Autosomal dominant APC gene mutations Variants Gardner Turcot

FAP - SurveillanceFAP - Surveillance Colon

Annual sigmoidoscopy age 10-12 yrs Prophylactic colectomy following polyp detection with

continued surveillance of rectum ileal pouch Duodenalgastric

EGD age 25 repeat 1-3 yrs Thyroid

Annual PE age 10 Hepatoblastoma

Annual screen by abd US amp AFP from birth to 5 yrs

Attenuated FAPAttenuated FAP 20 to 100 polyps usually more proximal

Onset later than FAP average AOO = 50 Lifetime risk of CRC = 80

Extracolonic tumors occur at same rate as FAP Variant of FAP mutations in same APC gene Surveillance

annual colonoscopy starting late teens or early 20rsquos Option of subtotal colectomy

Genetic Testing FAPAFAPGenetic Testing FAPAFAP Test an affected family member first

After genetic counseling and informed consent

APC gene testing can confirm a suspected diagnosis

Family members of a person with a known APC mutation can have mutation-specific testing

Genetic testing for children at risk for FAP can be considered before beginning colon screening

APC gene mutation inAPC gene mutation inAshkenazi JewsAshkenazi Jews

Missense mutation (I1307K) associated with increased risk of CRC and adenomas in Ashkenazi Jews (AJ)

Found in 6 of the general AJ population

12 of AJs with CRC

29 of AJs with CRC and a positive family history

Lifetime risk of CRC in mutation carrier is 10-20

Screening colonoscopy every 2-5 yrs starting at 35 yrs

MAP syndromeMYH geneMAP syndromeMYH gene Multiple adenomatous polyposis (MAP) syndrome

Autosomal recessive mutations in the MYH gene Median number of polyps = 55 Mean age of polyp diagnosis = 30-50 years Polyps mainly small mildly dysplastic tubular adenomas Some

tubulovillous hyperplastic serrated adenomas microadenomas

30 of individuals with 15-100 polyps have homozygous mutations in the MYH gene

Genetic testing should be offered if gt15 polyps (and APC gene testing negative)

Peutz-Jeghers SyndromePeutz-Jeghers Syndrome lt1 of all CRC cases Hamartomatous polyps of GI tract as early as 1st decade Mucocutaneous hyper pigmentation

lips mouth buccal mucosa fingers Usually seen in children lt 5 yrs

Cancer risk colon small intestine stomach pancreas breast ovaries uterus testes

lungs kidneys Mutations in STK11 gene

found in 70 of familial cases and 30-70 of sporadic cases

Familial Juvenile PolyposisFamilial Juvenile Polyposis

lt1 of all CRC cases

Autosomal dominant

5 or more juvenile polyps in colon or GI tract

Appear in 1st or 2nd decade

50 lifetime risk of CRC AOO in 30rsquos

Increased risk gastric GI pancreatic CA

~50 of cases have mutations in either the MADH4 or BMPR1A genes

Family Health HistoryFamily Health History

ldquoThe family tree has become the most important genetic test of all The more you know the more tools you have to practice preventive medicinerdquo

Donna Russo Certified Genetic Counselor NY Presbyterian-Columbia Hospital

Goal ClassificationGoal ClassificationAssessment Risk Classification Intervention

Family History

Average

Moderate

(ldquoFamilialrdquo)

HighGenetic

Personalized prevention recommendations

Standard prevention recommendations

Referral for genetic evaluation with personalized prevention recommendations

Consider Genetics Referral forConsider Genetics Referral for

Two or more family members with CRC at least one lt50

Three or more family members wCRC any age

Patient with colon cancer before 40 yrs

Endometrial cancer and family history of CRC lt50

Persons with more than one primary CRC lt50 yrs or with both endometrial CA and CRC

Family or personal history of CRC and one or more 1st degree relative with an HNPCC-related cancer one diagnosed lt50 yrs

Same side of family

Consider Genetics Referral forConsider Genetics Referral for

MSI andor IHC tumor results suspicious for HNPCC

Autosomal dominant pattern of cancers in the family

Persons with 15 or more adenomatous colorectal polyps

Persons with multiple hamartomatous or juvenile GI polyps

Persons with a family history of a known hereditary cancer syndrome

CRC Risk ManagementCRC Risk Management

Average Risk

1 No family history CRC OR2 One 2nd or 3rd degree relative with CRC

FOBT annually + flex sig every 5 years OR Colonoscopy every 10 years OR DCBE every 5 years

Age to Begin50 years

CRC Risk ManagementCRC Risk ManagementModerateFamily history Two 1st degree relatives with CRC any age

or one 1st degree relative with CRC lt 60- Colonoscopy every 5 yrs

One 1st degree relative with CRC gt60 or two 2nd degree relatives with CRC any age- Average risk screening

Or 5-10 yrs earlier than earliest case in family

Age to begin

40 years

40 years

CRC Risk ManagementCRC Risk Management

Age to Begin

HNPCC or suspected HNPCC 20-25 years 1 Colonoscopy every 1-2 yrs

2 Genetic counseling consider genetic testing

FAP or suspected FAP 10-12 years 1 Flex sig or colonoscopy every1-2 yrs

2 Genetic counseling consider genetic testing

Case 1 JoanCase 1 Joan Joan age 38 was recently diagnosed with

endometrial cancer Family history reveals

1 Paternal grandmother endometrial cancer age 50 2 Paternal uncle colon cancer age 48 3 Father colonoscopy at age 50 four adenomatous

polyps removed 4 No other significant history 5 Both sides of the family are Northern European

Caucasian

Pedigree Case 1Pedigree Case 1French Irish Scottish German English

88 yr

61 yr 63 yr

4 polyps

50 yrs 38 yr

35 yrDx 38

8 yr10 yr

CRC Dx 48

Dx 50

KEYKEY

Endometrial CA

Colorectal CA

Adenomatous Polyps

Case 1 AssessmentCase 1 Assessment Joan meets Amsterdam II Criteria and is at risk for HNPCC

Refer to genetics for cancer genetic counseling and discussion of genetic testing for HNPCC

Testing options

1 Direct gene testing of MLH1 and MSH2 OR

2 MSIIHC screening of tumor tissue with gene sequencing if MSI positive

Case 2 TedCase 2 Ted Ted is 30 and wants a colonoscopy because his mother

was just diagnosed with colon cancer after routine screening at age 54 Family history reveals

1 Paternal grandfather died of CRC at age 79

2 No hx of endometrial ovarian small bowel or ureterkidney cancer on either side of family

3 Two maternal aunts cervical cancer at ages 30 amp 34

4 Maternal grandmother breast cancer age 85

Pedigree Case 2Pedigree Case 2Italian Irish German

KEY

CRC

Breast CA

Cervical CA

84

d 58 MIBrCa 85 yrs

d87

55 58 60

Colon CA 54 yrs

Cervical CA 30 yrs

Cervical CA 32 yrs

34 yrs 30 yrs

CRC 79 d82

56

Case 2 TedCase 2 Ted Verify Diagnoses Obtain and review pathology reports on

all reported cancers whenever possible

If diagnoses are correct Ted has no family history indicative of a known colon cancer syndrome (HNPCC FAP other)

Tedrsquos lifetime risk of colorectal CA is increased 2 to 3 fold due to one affected first degree relative (gt50)

Moderatefamilial risk Screening by colonoscopy starting at age 40 or 10 yrs earlier than earliest case in family is reasonable

Chemo PreventionChemo Prevention Evidence that ASA NSAIDs Calcium and COX-2

inhibitors may reduce incidence of CA by reducing ofadenomas

1048707 40-50 risk reduction for developing colorectal CA regardless of location in colon age gender and race

Generally performed by RCTrsquos in patients with priorcolorectal CA followed for recurrence of adenomas

Diet fiber and antioxidant vitamins have not beenshown by RCTrsquos to decrease risk of recurrent adenomas

COX-2irsquos and Sulindac have been shown to reduce thenumber of adenomas found in FAP alone

1048707 Not effective for sporadic colon CA 1048707 Actually can cause regression of adenomas

HNPCCHNPCCClinical Diagnostic CriteriaClinical Diagnostic Criteria

Amsterdam II Criteria (3-2-1) 3 or more relatives with an HNPCC-related cancer

one of whom is a 1st degree relative of the other two 2 or more successive generations affected

1 or more cancers diagnosed before age 50

HNPCCHNPCC Caused by mutations or deletions in mismatched

repair (MMR) genes MSH2 MLH1 MSH6 (PMS2)

50 of families meeting Amsterdam II Criteria have detectable mutations

TestingScreening options Direct genetic testing of MMR genes (in select families) Initial screening of the tumor tissue by MSIIHC

MSIIHC ScreeningMSIIHC Screening Microsatellite Instability (MSI) on tumor tissue

can be used to screen for HNPCC in select cases

Immunohistochemistry (IHC) on tumor tissue

can be used to detect the presence or absence of the mismatch repair proteins (MSH2 MLH1 etc)

ldquoScreen positiverdquo individuals can be offered cancer genetic counselingassessment and targeted genetic testing

FAPFAP 1 in 10000 incidence 100rsquos to 1000rsquos of colonic adenomas by teens

Cancer risk colon gastric duodenum (periampulla) small bowel pancreas papillary thyroid childhood hepatoblastoma

7 risk of CRC by 21 yrs 93 by 50 yrs Autosomal dominant APC gene mutations Variants Gardner Turcot

FAP - SurveillanceFAP - Surveillance Colon

Annual sigmoidoscopy age 10-12 yrs Prophylactic colectomy following polyp detection with

continued surveillance of rectum ileal pouch Duodenalgastric

EGD age 25 repeat 1-3 yrs Thyroid

Annual PE age 10 Hepatoblastoma

Annual screen by abd US amp AFP from birth to 5 yrs

Attenuated FAPAttenuated FAP 20 to 100 polyps usually more proximal

Onset later than FAP average AOO = 50 Lifetime risk of CRC = 80

Extracolonic tumors occur at same rate as FAP Variant of FAP mutations in same APC gene Surveillance

annual colonoscopy starting late teens or early 20rsquos Option of subtotal colectomy

Genetic Testing FAPAFAPGenetic Testing FAPAFAP Test an affected family member first

After genetic counseling and informed consent

APC gene testing can confirm a suspected diagnosis

Family members of a person with a known APC mutation can have mutation-specific testing

Genetic testing for children at risk for FAP can be considered before beginning colon screening

APC gene mutation inAPC gene mutation inAshkenazi JewsAshkenazi Jews

Missense mutation (I1307K) associated with increased risk of CRC and adenomas in Ashkenazi Jews (AJ)

Found in 6 of the general AJ population

12 of AJs with CRC

29 of AJs with CRC and a positive family history

Lifetime risk of CRC in mutation carrier is 10-20

Screening colonoscopy every 2-5 yrs starting at 35 yrs

MAP syndromeMYH geneMAP syndromeMYH gene Multiple adenomatous polyposis (MAP) syndrome

Autosomal recessive mutations in the MYH gene Median number of polyps = 55 Mean age of polyp diagnosis = 30-50 years Polyps mainly small mildly dysplastic tubular adenomas Some

tubulovillous hyperplastic serrated adenomas microadenomas

30 of individuals with 15-100 polyps have homozygous mutations in the MYH gene

Genetic testing should be offered if gt15 polyps (and APC gene testing negative)

Peutz-Jeghers SyndromePeutz-Jeghers Syndrome lt1 of all CRC cases Hamartomatous polyps of GI tract as early as 1st decade Mucocutaneous hyper pigmentation

lips mouth buccal mucosa fingers Usually seen in children lt 5 yrs

Cancer risk colon small intestine stomach pancreas breast ovaries uterus testes

lungs kidneys Mutations in STK11 gene

found in 70 of familial cases and 30-70 of sporadic cases

Familial Juvenile PolyposisFamilial Juvenile Polyposis

lt1 of all CRC cases

Autosomal dominant

5 or more juvenile polyps in colon or GI tract

Appear in 1st or 2nd decade

50 lifetime risk of CRC AOO in 30rsquos

Increased risk gastric GI pancreatic CA

~50 of cases have mutations in either the MADH4 or BMPR1A genes

Family Health HistoryFamily Health History

ldquoThe family tree has become the most important genetic test of all The more you know the more tools you have to practice preventive medicinerdquo

Donna Russo Certified Genetic Counselor NY Presbyterian-Columbia Hospital

Goal ClassificationGoal ClassificationAssessment Risk Classification Intervention

Family History

Average

Moderate

(ldquoFamilialrdquo)

HighGenetic

Personalized prevention recommendations

Standard prevention recommendations

Referral for genetic evaluation with personalized prevention recommendations

Consider Genetics Referral forConsider Genetics Referral for

Two or more family members with CRC at least one lt50

Three or more family members wCRC any age

Patient with colon cancer before 40 yrs

Endometrial cancer and family history of CRC lt50

Persons with more than one primary CRC lt50 yrs or with both endometrial CA and CRC

Family or personal history of CRC and one or more 1st degree relative with an HNPCC-related cancer one diagnosed lt50 yrs

Same side of family

Consider Genetics Referral forConsider Genetics Referral for

MSI andor IHC tumor results suspicious for HNPCC

Autosomal dominant pattern of cancers in the family

Persons with 15 or more adenomatous colorectal polyps

Persons with multiple hamartomatous or juvenile GI polyps

Persons with a family history of a known hereditary cancer syndrome

CRC Risk ManagementCRC Risk Management

Average Risk

1 No family history CRC OR2 One 2nd or 3rd degree relative with CRC

FOBT annually + flex sig every 5 years OR Colonoscopy every 10 years OR DCBE every 5 years

Age to Begin50 years

CRC Risk ManagementCRC Risk ManagementModerateFamily history Two 1st degree relatives with CRC any age

or one 1st degree relative with CRC lt 60- Colonoscopy every 5 yrs

One 1st degree relative with CRC gt60 or two 2nd degree relatives with CRC any age- Average risk screening

Or 5-10 yrs earlier than earliest case in family

Age to begin

40 years

40 years

CRC Risk ManagementCRC Risk Management

Age to Begin

HNPCC or suspected HNPCC 20-25 years 1 Colonoscopy every 1-2 yrs

2 Genetic counseling consider genetic testing

FAP or suspected FAP 10-12 years 1 Flex sig or colonoscopy every1-2 yrs

2 Genetic counseling consider genetic testing

Case 1 JoanCase 1 Joan Joan age 38 was recently diagnosed with

endometrial cancer Family history reveals

1 Paternal grandmother endometrial cancer age 50 2 Paternal uncle colon cancer age 48 3 Father colonoscopy at age 50 four adenomatous

polyps removed 4 No other significant history 5 Both sides of the family are Northern European

Caucasian

Pedigree Case 1Pedigree Case 1French Irish Scottish German English

88 yr

61 yr 63 yr

4 polyps

50 yrs 38 yr

35 yrDx 38

8 yr10 yr

CRC Dx 48

Dx 50

KEYKEY

Endometrial CA

Colorectal CA

Adenomatous Polyps

Case 1 AssessmentCase 1 Assessment Joan meets Amsterdam II Criteria and is at risk for HNPCC

Refer to genetics for cancer genetic counseling and discussion of genetic testing for HNPCC

Testing options

1 Direct gene testing of MLH1 and MSH2 OR

2 MSIIHC screening of tumor tissue with gene sequencing if MSI positive

Case 2 TedCase 2 Ted Ted is 30 and wants a colonoscopy because his mother

was just diagnosed with colon cancer after routine screening at age 54 Family history reveals

1 Paternal grandfather died of CRC at age 79

2 No hx of endometrial ovarian small bowel or ureterkidney cancer on either side of family

3 Two maternal aunts cervical cancer at ages 30 amp 34

4 Maternal grandmother breast cancer age 85

Pedigree Case 2Pedigree Case 2Italian Irish German

KEY

CRC

Breast CA

Cervical CA

84

d 58 MIBrCa 85 yrs

d87

55 58 60

Colon CA 54 yrs

Cervical CA 30 yrs

Cervical CA 32 yrs

34 yrs 30 yrs

CRC 79 d82

56

Case 2 TedCase 2 Ted Verify Diagnoses Obtain and review pathology reports on

all reported cancers whenever possible

If diagnoses are correct Ted has no family history indicative of a known colon cancer syndrome (HNPCC FAP other)

Tedrsquos lifetime risk of colorectal CA is increased 2 to 3 fold due to one affected first degree relative (gt50)

Moderatefamilial risk Screening by colonoscopy starting at age 40 or 10 yrs earlier than earliest case in family is reasonable

Chemo PreventionChemo Prevention Evidence that ASA NSAIDs Calcium and COX-2

inhibitors may reduce incidence of CA by reducing ofadenomas

1048707 40-50 risk reduction for developing colorectal CA regardless of location in colon age gender and race

Generally performed by RCTrsquos in patients with priorcolorectal CA followed for recurrence of adenomas

Diet fiber and antioxidant vitamins have not beenshown by RCTrsquos to decrease risk of recurrent adenomas

COX-2irsquos and Sulindac have been shown to reduce thenumber of adenomas found in FAP alone

1048707 Not effective for sporadic colon CA 1048707 Actually can cause regression of adenomas

HNPCCHNPCC Caused by mutations or deletions in mismatched

repair (MMR) genes MSH2 MLH1 MSH6 (PMS2)

50 of families meeting Amsterdam II Criteria have detectable mutations

TestingScreening options Direct genetic testing of MMR genes (in select families) Initial screening of the tumor tissue by MSIIHC

MSIIHC ScreeningMSIIHC Screening Microsatellite Instability (MSI) on tumor tissue

can be used to screen for HNPCC in select cases

Immunohistochemistry (IHC) on tumor tissue

can be used to detect the presence or absence of the mismatch repair proteins (MSH2 MLH1 etc)

ldquoScreen positiverdquo individuals can be offered cancer genetic counselingassessment and targeted genetic testing

FAPFAP 1 in 10000 incidence 100rsquos to 1000rsquos of colonic adenomas by teens

Cancer risk colon gastric duodenum (periampulla) small bowel pancreas papillary thyroid childhood hepatoblastoma

7 risk of CRC by 21 yrs 93 by 50 yrs Autosomal dominant APC gene mutations Variants Gardner Turcot

FAP - SurveillanceFAP - Surveillance Colon

Annual sigmoidoscopy age 10-12 yrs Prophylactic colectomy following polyp detection with

continued surveillance of rectum ileal pouch Duodenalgastric

EGD age 25 repeat 1-3 yrs Thyroid

Annual PE age 10 Hepatoblastoma

Annual screen by abd US amp AFP from birth to 5 yrs

Attenuated FAPAttenuated FAP 20 to 100 polyps usually more proximal

Onset later than FAP average AOO = 50 Lifetime risk of CRC = 80

Extracolonic tumors occur at same rate as FAP Variant of FAP mutations in same APC gene Surveillance

annual colonoscopy starting late teens or early 20rsquos Option of subtotal colectomy

Genetic Testing FAPAFAPGenetic Testing FAPAFAP Test an affected family member first

After genetic counseling and informed consent

APC gene testing can confirm a suspected diagnosis

Family members of a person with a known APC mutation can have mutation-specific testing

Genetic testing for children at risk for FAP can be considered before beginning colon screening

APC gene mutation inAPC gene mutation inAshkenazi JewsAshkenazi Jews

Missense mutation (I1307K) associated with increased risk of CRC and adenomas in Ashkenazi Jews (AJ)

Found in 6 of the general AJ population

12 of AJs with CRC

29 of AJs with CRC and a positive family history

Lifetime risk of CRC in mutation carrier is 10-20

Screening colonoscopy every 2-5 yrs starting at 35 yrs

MAP syndromeMYH geneMAP syndromeMYH gene Multiple adenomatous polyposis (MAP) syndrome

Autosomal recessive mutations in the MYH gene Median number of polyps = 55 Mean age of polyp diagnosis = 30-50 years Polyps mainly small mildly dysplastic tubular adenomas Some

tubulovillous hyperplastic serrated adenomas microadenomas

30 of individuals with 15-100 polyps have homozygous mutations in the MYH gene

Genetic testing should be offered if gt15 polyps (and APC gene testing negative)

Peutz-Jeghers SyndromePeutz-Jeghers Syndrome lt1 of all CRC cases Hamartomatous polyps of GI tract as early as 1st decade Mucocutaneous hyper pigmentation

lips mouth buccal mucosa fingers Usually seen in children lt 5 yrs

Cancer risk colon small intestine stomach pancreas breast ovaries uterus testes

lungs kidneys Mutations in STK11 gene

found in 70 of familial cases and 30-70 of sporadic cases

Familial Juvenile PolyposisFamilial Juvenile Polyposis

lt1 of all CRC cases

Autosomal dominant

5 or more juvenile polyps in colon or GI tract

Appear in 1st or 2nd decade

50 lifetime risk of CRC AOO in 30rsquos

Increased risk gastric GI pancreatic CA

~50 of cases have mutations in either the MADH4 or BMPR1A genes

Family Health HistoryFamily Health History

ldquoThe family tree has become the most important genetic test of all The more you know the more tools you have to practice preventive medicinerdquo

Donna Russo Certified Genetic Counselor NY Presbyterian-Columbia Hospital

Goal ClassificationGoal ClassificationAssessment Risk Classification Intervention

Family History

Average

Moderate

(ldquoFamilialrdquo)

HighGenetic

Personalized prevention recommendations

Standard prevention recommendations

Referral for genetic evaluation with personalized prevention recommendations

Consider Genetics Referral forConsider Genetics Referral for

Two or more family members with CRC at least one lt50

Three or more family members wCRC any age

Patient with colon cancer before 40 yrs

Endometrial cancer and family history of CRC lt50

Persons with more than one primary CRC lt50 yrs or with both endometrial CA and CRC

Family or personal history of CRC and one or more 1st degree relative with an HNPCC-related cancer one diagnosed lt50 yrs

Same side of family

Consider Genetics Referral forConsider Genetics Referral for

MSI andor IHC tumor results suspicious for HNPCC

Autosomal dominant pattern of cancers in the family

Persons with 15 or more adenomatous colorectal polyps

Persons with multiple hamartomatous or juvenile GI polyps

Persons with a family history of a known hereditary cancer syndrome

CRC Risk ManagementCRC Risk Management

Average Risk

1 No family history CRC OR2 One 2nd or 3rd degree relative with CRC

FOBT annually + flex sig every 5 years OR Colonoscopy every 10 years OR DCBE every 5 years

Age to Begin50 years

CRC Risk ManagementCRC Risk ManagementModerateFamily history Two 1st degree relatives with CRC any age

or one 1st degree relative with CRC lt 60- Colonoscopy every 5 yrs

One 1st degree relative with CRC gt60 or two 2nd degree relatives with CRC any age- Average risk screening

Or 5-10 yrs earlier than earliest case in family

Age to begin

40 years

40 years

CRC Risk ManagementCRC Risk Management

Age to Begin

HNPCC or suspected HNPCC 20-25 years 1 Colonoscopy every 1-2 yrs

2 Genetic counseling consider genetic testing

FAP or suspected FAP 10-12 years 1 Flex sig or colonoscopy every1-2 yrs

2 Genetic counseling consider genetic testing

Case 1 JoanCase 1 Joan Joan age 38 was recently diagnosed with

endometrial cancer Family history reveals

1 Paternal grandmother endometrial cancer age 50 2 Paternal uncle colon cancer age 48 3 Father colonoscopy at age 50 four adenomatous

polyps removed 4 No other significant history 5 Both sides of the family are Northern European

Caucasian

Pedigree Case 1Pedigree Case 1French Irish Scottish German English

88 yr

61 yr 63 yr

4 polyps

50 yrs 38 yr

35 yrDx 38

8 yr10 yr

CRC Dx 48

Dx 50

KEYKEY

Endometrial CA

Colorectal CA

Adenomatous Polyps

Case 1 AssessmentCase 1 Assessment Joan meets Amsterdam II Criteria and is at risk for HNPCC

Refer to genetics for cancer genetic counseling and discussion of genetic testing for HNPCC

Testing options

1 Direct gene testing of MLH1 and MSH2 OR

2 MSIIHC screening of tumor tissue with gene sequencing if MSI positive

Case 2 TedCase 2 Ted Ted is 30 and wants a colonoscopy because his mother

was just diagnosed with colon cancer after routine screening at age 54 Family history reveals

1 Paternal grandfather died of CRC at age 79

2 No hx of endometrial ovarian small bowel or ureterkidney cancer on either side of family

3 Two maternal aunts cervical cancer at ages 30 amp 34

4 Maternal grandmother breast cancer age 85

Pedigree Case 2Pedigree Case 2Italian Irish German

KEY

CRC

Breast CA

Cervical CA

84

d 58 MIBrCa 85 yrs

d87

55 58 60

Colon CA 54 yrs

Cervical CA 30 yrs

Cervical CA 32 yrs

34 yrs 30 yrs

CRC 79 d82

56

Case 2 TedCase 2 Ted Verify Diagnoses Obtain and review pathology reports on

all reported cancers whenever possible

If diagnoses are correct Ted has no family history indicative of a known colon cancer syndrome (HNPCC FAP other)

Tedrsquos lifetime risk of colorectal CA is increased 2 to 3 fold due to one affected first degree relative (gt50)

Moderatefamilial risk Screening by colonoscopy starting at age 40 or 10 yrs earlier than earliest case in family is reasonable

Chemo PreventionChemo Prevention Evidence that ASA NSAIDs Calcium and COX-2

inhibitors may reduce incidence of CA by reducing ofadenomas

1048707 40-50 risk reduction for developing colorectal CA regardless of location in colon age gender and race

Generally performed by RCTrsquos in patients with priorcolorectal CA followed for recurrence of adenomas

Diet fiber and antioxidant vitamins have not beenshown by RCTrsquos to decrease risk of recurrent adenomas

COX-2irsquos and Sulindac have been shown to reduce thenumber of adenomas found in FAP alone

1048707 Not effective for sporadic colon CA 1048707 Actually can cause regression of adenomas

MSIIHC ScreeningMSIIHC Screening Microsatellite Instability (MSI) on tumor tissue

can be used to screen for HNPCC in select cases

Immunohistochemistry (IHC) on tumor tissue

can be used to detect the presence or absence of the mismatch repair proteins (MSH2 MLH1 etc)

ldquoScreen positiverdquo individuals can be offered cancer genetic counselingassessment and targeted genetic testing

FAPFAP 1 in 10000 incidence 100rsquos to 1000rsquos of colonic adenomas by teens

Cancer risk colon gastric duodenum (periampulla) small bowel pancreas papillary thyroid childhood hepatoblastoma

7 risk of CRC by 21 yrs 93 by 50 yrs Autosomal dominant APC gene mutations Variants Gardner Turcot

FAP - SurveillanceFAP - Surveillance Colon

Annual sigmoidoscopy age 10-12 yrs Prophylactic colectomy following polyp detection with

continued surveillance of rectum ileal pouch Duodenalgastric

EGD age 25 repeat 1-3 yrs Thyroid

Annual PE age 10 Hepatoblastoma

Annual screen by abd US amp AFP from birth to 5 yrs

Attenuated FAPAttenuated FAP 20 to 100 polyps usually more proximal

Onset later than FAP average AOO = 50 Lifetime risk of CRC = 80

Extracolonic tumors occur at same rate as FAP Variant of FAP mutations in same APC gene Surveillance

annual colonoscopy starting late teens or early 20rsquos Option of subtotal colectomy

Genetic Testing FAPAFAPGenetic Testing FAPAFAP Test an affected family member first

After genetic counseling and informed consent

APC gene testing can confirm a suspected diagnosis

Family members of a person with a known APC mutation can have mutation-specific testing

Genetic testing for children at risk for FAP can be considered before beginning colon screening

APC gene mutation inAPC gene mutation inAshkenazi JewsAshkenazi Jews

Missense mutation (I1307K) associated with increased risk of CRC and adenomas in Ashkenazi Jews (AJ)

Found in 6 of the general AJ population

12 of AJs with CRC

29 of AJs with CRC and a positive family history

Lifetime risk of CRC in mutation carrier is 10-20

Screening colonoscopy every 2-5 yrs starting at 35 yrs

MAP syndromeMYH geneMAP syndromeMYH gene Multiple adenomatous polyposis (MAP) syndrome

Autosomal recessive mutations in the MYH gene Median number of polyps = 55 Mean age of polyp diagnosis = 30-50 years Polyps mainly small mildly dysplastic tubular adenomas Some

tubulovillous hyperplastic serrated adenomas microadenomas

30 of individuals with 15-100 polyps have homozygous mutations in the MYH gene

Genetic testing should be offered if gt15 polyps (and APC gene testing negative)

Peutz-Jeghers SyndromePeutz-Jeghers Syndrome lt1 of all CRC cases Hamartomatous polyps of GI tract as early as 1st decade Mucocutaneous hyper pigmentation

lips mouth buccal mucosa fingers Usually seen in children lt 5 yrs

Cancer risk colon small intestine stomach pancreas breast ovaries uterus testes

lungs kidneys Mutations in STK11 gene

found in 70 of familial cases and 30-70 of sporadic cases

Familial Juvenile PolyposisFamilial Juvenile Polyposis

lt1 of all CRC cases

Autosomal dominant

5 or more juvenile polyps in colon or GI tract

Appear in 1st or 2nd decade

50 lifetime risk of CRC AOO in 30rsquos

Increased risk gastric GI pancreatic CA

~50 of cases have mutations in either the MADH4 or BMPR1A genes

Family Health HistoryFamily Health History

ldquoThe family tree has become the most important genetic test of all The more you know the more tools you have to practice preventive medicinerdquo

Donna Russo Certified Genetic Counselor NY Presbyterian-Columbia Hospital

Goal ClassificationGoal ClassificationAssessment Risk Classification Intervention

Family History

Average

Moderate

(ldquoFamilialrdquo)

HighGenetic

Personalized prevention recommendations

Standard prevention recommendations

Referral for genetic evaluation with personalized prevention recommendations

Consider Genetics Referral forConsider Genetics Referral for

Two or more family members with CRC at least one lt50

Three or more family members wCRC any age

Patient with colon cancer before 40 yrs

Endometrial cancer and family history of CRC lt50

Persons with more than one primary CRC lt50 yrs or with both endometrial CA and CRC

Family or personal history of CRC and one or more 1st degree relative with an HNPCC-related cancer one diagnosed lt50 yrs

Same side of family

Consider Genetics Referral forConsider Genetics Referral for

MSI andor IHC tumor results suspicious for HNPCC

Autosomal dominant pattern of cancers in the family

Persons with 15 or more adenomatous colorectal polyps

Persons with multiple hamartomatous or juvenile GI polyps

Persons with a family history of a known hereditary cancer syndrome

CRC Risk ManagementCRC Risk Management

Average Risk

1 No family history CRC OR2 One 2nd or 3rd degree relative with CRC

FOBT annually + flex sig every 5 years OR Colonoscopy every 10 years OR DCBE every 5 years

Age to Begin50 years

CRC Risk ManagementCRC Risk ManagementModerateFamily history Two 1st degree relatives with CRC any age

or one 1st degree relative with CRC lt 60- Colonoscopy every 5 yrs

One 1st degree relative with CRC gt60 or two 2nd degree relatives with CRC any age- Average risk screening

Or 5-10 yrs earlier than earliest case in family

Age to begin

40 years

40 years

CRC Risk ManagementCRC Risk Management

Age to Begin

HNPCC or suspected HNPCC 20-25 years 1 Colonoscopy every 1-2 yrs

2 Genetic counseling consider genetic testing

FAP or suspected FAP 10-12 years 1 Flex sig or colonoscopy every1-2 yrs

2 Genetic counseling consider genetic testing

Case 1 JoanCase 1 Joan Joan age 38 was recently diagnosed with

endometrial cancer Family history reveals

1 Paternal grandmother endometrial cancer age 50 2 Paternal uncle colon cancer age 48 3 Father colonoscopy at age 50 four adenomatous

polyps removed 4 No other significant history 5 Both sides of the family are Northern European

Caucasian

Pedigree Case 1Pedigree Case 1French Irish Scottish German English

88 yr

61 yr 63 yr

4 polyps

50 yrs 38 yr

35 yrDx 38

8 yr10 yr

CRC Dx 48

Dx 50

KEYKEY

Endometrial CA

Colorectal CA

Adenomatous Polyps

Case 1 AssessmentCase 1 Assessment Joan meets Amsterdam II Criteria and is at risk for HNPCC

Refer to genetics for cancer genetic counseling and discussion of genetic testing for HNPCC

Testing options

1 Direct gene testing of MLH1 and MSH2 OR

2 MSIIHC screening of tumor tissue with gene sequencing if MSI positive

Case 2 TedCase 2 Ted Ted is 30 and wants a colonoscopy because his mother

was just diagnosed with colon cancer after routine screening at age 54 Family history reveals

1 Paternal grandfather died of CRC at age 79

2 No hx of endometrial ovarian small bowel or ureterkidney cancer on either side of family

3 Two maternal aunts cervical cancer at ages 30 amp 34

4 Maternal grandmother breast cancer age 85

Pedigree Case 2Pedigree Case 2Italian Irish German

KEY

CRC

Breast CA

Cervical CA

84

d 58 MIBrCa 85 yrs

d87

55 58 60

Colon CA 54 yrs

Cervical CA 30 yrs

Cervical CA 32 yrs

34 yrs 30 yrs

CRC 79 d82

56

Case 2 TedCase 2 Ted Verify Diagnoses Obtain and review pathology reports on

all reported cancers whenever possible

If diagnoses are correct Ted has no family history indicative of a known colon cancer syndrome (HNPCC FAP other)

Tedrsquos lifetime risk of colorectal CA is increased 2 to 3 fold due to one affected first degree relative (gt50)

Moderatefamilial risk Screening by colonoscopy starting at age 40 or 10 yrs earlier than earliest case in family is reasonable

Chemo PreventionChemo Prevention Evidence that ASA NSAIDs Calcium and COX-2

inhibitors may reduce incidence of CA by reducing ofadenomas

1048707 40-50 risk reduction for developing colorectal CA regardless of location in colon age gender and race

Generally performed by RCTrsquos in patients with priorcolorectal CA followed for recurrence of adenomas

Diet fiber and antioxidant vitamins have not beenshown by RCTrsquos to decrease risk of recurrent adenomas

COX-2irsquos and Sulindac have been shown to reduce thenumber of adenomas found in FAP alone

1048707 Not effective for sporadic colon CA 1048707 Actually can cause regression of adenomas

FAPFAP 1 in 10000 incidence 100rsquos to 1000rsquos of colonic adenomas by teens

Cancer risk colon gastric duodenum (periampulla) small bowel pancreas papillary thyroid childhood hepatoblastoma

7 risk of CRC by 21 yrs 93 by 50 yrs Autosomal dominant APC gene mutations Variants Gardner Turcot

FAP - SurveillanceFAP - Surveillance Colon

Annual sigmoidoscopy age 10-12 yrs Prophylactic colectomy following polyp detection with

continued surveillance of rectum ileal pouch Duodenalgastric

EGD age 25 repeat 1-3 yrs Thyroid

Annual PE age 10 Hepatoblastoma

Annual screen by abd US amp AFP from birth to 5 yrs

Attenuated FAPAttenuated FAP 20 to 100 polyps usually more proximal

Onset later than FAP average AOO = 50 Lifetime risk of CRC = 80

Extracolonic tumors occur at same rate as FAP Variant of FAP mutations in same APC gene Surveillance

annual colonoscopy starting late teens or early 20rsquos Option of subtotal colectomy

Genetic Testing FAPAFAPGenetic Testing FAPAFAP Test an affected family member first

After genetic counseling and informed consent

APC gene testing can confirm a suspected diagnosis

Family members of a person with a known APC mutation can have mutation-specific testing

Genetic testing for children at risk for FAP can be considered before beginning colon screening

APC gene mutation inAPC gene mutation inAshkenazi JewsAshkenazi Jews

Missense mutation (I1307K) associated with increased risk of CRC and adenomas in Ashkenazi Jews (AJ)

Found in 6 of the general AJ population

12 of AJs with CRC

29 of AJs with CRC and a positive family history

Lifetime risk of CRC in mutation carrier is 10-20

Screening colonoscopy every 2-5 yrs starting at 35 yrs

MAP syndromeMYH geneMAP syndromeMYH gene Multiple adenomatous polyposis (MAP) syndrome

Autosomal recessive mutations in the MYH gene Median number of polyps = 55 Mean age of polyp diagnosis = 30-50 years Polyps mainly small mildly dysplastic tubular adenomas Some

tubulovillous hyperplastic serrated adenomas microadenomas

30 of individuals with 15-100 polyps have homozygous mutations in the MYH gene

Genetic testing should be offered if gt15 polyps (and APC gene testing negative)

Peutz-Jeghers SyndromePeutz-Jeghers Syndrome lt1 of all CRC cases Hamartomatous polyps of GI tract as early as 1st decade Mucocutaneous hyper pigmentation

lips mouth buccal mucosa fingers Usually seen in children lt 5 yrs

Cancer risk colon small intestine stomach pancreas breast ovaries uterus testes

lungs kidneys Mutations in STK11 gene

found in 70 of familial cases and 30-70 of sporadic cases

Familial Juvenile PolyposisFamilial Juvenile Polyposis

lt1 of all CRC cases

Autosomal dominant

5 or more juvenile polyps in colon or GI tract

Appear in 1st or 2nd decade

50 lifetime risk of CRC AOO in 30rsquos

Increased risk gastric GI pancreatic CA

~50 of cases have mutations in either the MADH4 or BMPR1A genes

Family Health HistoryFamily Health History

ldquoThe family tree has become the most important genetic test of all The more you know the more tools you have to practice preventive medicinerdquo

Donna Russo Certified Genetic Counselor NY Presbyterian-Columbia Hospital

Goal ClassificationGoal ClassificationAssessment Risk Classification Intervention

Family History

Average

Moderate

(ldquoFamilialrdquo)

HighGenetic

Personalized prevention recommendations

Standard prevention recommendations

Referral for genetic evaluation with personalized prevention recommendations

Consider Genetics Referral forConsider Genetics Referral for

Two or more family members with CRC at least one lt50

Three or more family members wCRC any age

Patient with colon cancer before 40 yrs

Endometrial cancer and family history of CRC lt50

Persons with more than one primary CRC lt50 yrs or with both endometrial CA and CRC

Family or personal history of CRC and one or more 1st degree relative with an HNPCC-related cancer one diagnosed lt50 yrs

Same side of family

Consider Genetics Referral forConsider Genetics Referral for

MSI andor IHC tumor results suspicious for HNPCC

Autosomal dominant pattern of cancers in the family

Persons with 15 or more adenomatous colorectal polyps

Persons with multiple hamartomatous or juvenile GI polyps

Persons with a family history of a known hereditary cancer syndrome

CRC Risk ManagementCRC Risk Management

Average Risk

1 No family history CRC OR2 One 2nd or 3rd degree relative with CRC

FOBT annually + flex sig every 5 years OR Colonoscopy every 10 years OR DCBE every 5 years

Age to Begin50 years

CRC Risk ManagementCRC Risk ManagementModerateFamily history Two 1st degree relatives with CRC any age

or one 1st degree relative with CRC lt 60- Colonoscopy every 5 yrs

One 1st degree relative with CRC gt60 or two 2nd degree relatives with CRC any age- Average risk screening

Or 5-10 yrs earlier than earliest case in family

Age to begin

40 years

40 years

CRC Risk ManagementCRC Risk Management

Age to Begin

HNPCC or suspected HNPCC 20-25 years 1 Colonoscopy every 1-2 yrs

2 Genetic counseling consider genetic testing

FAP or suspected FAP 10-12 years 1 Flex sig or colonoscopy every1-2 yrs

2 Genetic counseling consider genetic testing

Case 1 JoanCase 1 Joan Joan age 38 was recently diagnosed with

endometrial cancer Family history reveals

1 Paternal grandmother endometrial cancer age 50 2 Paternal uncle colon cancer age 48 3 Father colonoscopy at age 50 four adenomatous

polyps removed 4 No other significant history 5 Both sides of the family are Northern European

Caucasian

Pedigree Case 1Pedigree Case 1French Irish Scottish German English

88 yr

61 yr 63 yr

4 polyps

50 yrs 38 yr

35 yrDx 38

8 yr10 yr

CRC Dx 48

Dx 50

KEYKEY

Endometrial CA

Colorectal CA

Adenomatous Polyps

Case 1 AssessmentCase 1 Assessment Joan meets Amsterdam II Criteria and is at risk for HNPCC

Refer to genetics for cancer genetic counseling and discussion of genetic testing for HNPCC

Testing options

1 Direct gene testing of MLH1 and MSH2 OR

2 MSIIHC screening of tumor tissue with gene sequencing if MSI positive

Case 2 TedCase 2 Ted Ted is 30 and wants a colonoscopy because his mother

was just diagnosed with colon cancer after routine screening at age 54 Family history reveals

1 Paternal grandfather died of CRC at age 79

2 No hx of endometrial ovarian small bowel or ureterkidney cancer on either side of family

3 Two maternal aunts cervical cancer at ages 30 amp 34

4 Maternal grandmother breast cancer age 85

Pedigree Case 2Pedigree Case 2Italian Irish German

KEY

CRC

Breast CA

Cervical CA

84

d 58 MIBrCa 85 yrs

d87

55 58 60

Colon CA 54 yrs

Cervical CA 30 yrs

Cervical CA 32 yrs

34 yrs 30 yrs

CRC 79 d82

56

Case 2 TedCase 2 Ted Verify Diagnoses Obtain and review pathology reports on

all reported cancers whenever possible

If diagnoses are correct Ted has no family history indicative of a known colon cancer syndrome (HNPCC FAP other)

Tedrsquos lifetime risk of colorectal CA is increased 2 to 3 fold due to one affected first degree relative (gt50)

Moderatefamilial risk Screening by colonoscopy starting at age 40 or 10 yrs earlier than earliest case in family is reasonable

Chemo PreventionChemo Prevention Evidence that ASA NSAIDs Calcium and COX-2

inhibitors may reduce incidence of CA by reducing ofadenomas

1048707 40-50 risk reduction for developing colorectal CA regardless of location in colon age gender and race

Generally performed by RCTrsquos in patients with priorcolorectal CA followed for recurrence of adenomas

Diet fiber and antioxidant vitamins have not beenshown by RCTrsquos to decrease risk of recurrent adenomas

COX-2irsquos and Sulindac have been shown to reduce thenumber of adenomas found in FAP alone

1048707 Not effective for sporadic colon CA 1048707 Actually can cause regression of adenomas

FAP - SurveillanceFAP - Surveillance Colon

Annual sigmoidoscopy age 10-12 yrs Prophylactic colectomy following polyp detection with

continued surveillance of rectum ileal pouch Duodenalgastric

EGD age 25 repeat 1-3 yrs Thyroid

Annual PE age 10 Hepatoblastoma

Annual screen by abd US amp AFP from birth to 5 yrs

Attenuated FAPAttenuated FAP 20 to 100 polyps usually more proximal

Onset later than FAP average AOO = 50 Lifetime risk of CRC = 80

Extracolonic tumors occur at same rate as FAP Variant of FAP mutations in same APC gene Surveillance

annual colonoscopy starting late teens or early 20rsquos Option of subtotal colectomy

Genetic Testing FAPAFAPGenetic Testing FAPAFAP Test an affected family member first

After genetic counseling and informed consent

APC gene testing can confirm a suspected diagnosis

Family members of a person with a known APC mutation can have mutation-specific testing

Genetic testing for children at risk for FAP can be considered before beginning colon screening

APC gene mutation inAPC gene mutation inAshkenazi JewsAshkenazi Jews

Missense mutation (I1307K) associated with increased risk of CRC and adenomas in Ashkenazi Jews (AJ)

Found in 6 of the general AJ population

12 of AJs with CRC

29 of AJs with CRC and a positive family history

Lifetime risk of CRC in mutation carrier is 10-20

Screening colonoscopy every 2-5 yrs starting at 35 yrs

MAP syndromeMYH geneMAP syndromeMYH gene Multiple adenomatous polyposis (MAP) syndrome

Autosomal recessive mutations in the MYH gene Median number of polyps = 55 Mean age of polyp diagnosis = 30-50 years Polyps mainly small mildly dysplastic tubular adenomas Some

tubulovillous hyperplastic serrated adenomas microadenomas

30 of individuals with 15-100 polyps have homozygous mutations in the MYH gene

Genetic testing should be offered if gt15 polyps (and APC gene testing negative)

Peutz-Jeghers SyndromePeutz-Jeghers Syndrome lt1 of all CRC cases Hamartomatous polyps of GI tract as early as 1st decade Mucocutaneous hyper pigmentation

lips mouth buccal mucosa fingers Usually seen in children lt 5 yrs

Cancer risk colon small intestine stomach pancreas breast ovaries uterus testes

lungs kidneys Mutations in STK11 gene

found in 70 of familial cases and 30-70 of sporadic cases

Familial Juvenile PolyposisFamilial Juvenile Polyposis

lt1 of all CRC cases

Autosomal dominant

5 or more juvenile polyps in colon or GI tract

Appear in 1st or 2nd decade

50 lifetime risk of CRC AOO in 30rsquos

Increased risk gastric GI pancreatic CA

~50 of cases have mutations in either the MADH4 or BMPR1A genes

Family Health HistoryFamily Health History

ldquoThe family tree has become the most important genetic test of all The more you know the more tools you have to practice preventive medicinerdquo

Donna Russo Certified Genetic Counselor NY Presbyterian-Columbia Hospital

Goal ClassificationGoal ClassificationAssessment Risk Classification Intervention

Family History

Average

Moderate

(ldquoFamilialrdquo)

HighGenetic

Personalized prevention recommendations

Standard prevention recommendations

Referral for genetic evaluation with personalized prevention recommendations

Consider Genetics Referral forConsider Genetics Referral for

Two or more family members with CRC at least one lt50

Three or more family members wCRC any age

Patient with colon cancer before 40 yrs

Endometrial cancer and family history of CRC lt50

Persons with more than one primary CRC lt50 yrs or with both endometrial CA and CRC

Family or personal history of CRC and one or more 1st degree relative with an HNPCC-related cancer one diagnosed lt50 yrs

Same side of family

Consider Genetics Referral forConsider Genetics Referral for

MSI andor IHC tumor results suspicious for HNPCC

Autosomal dominant pattern of cancers in the family

Persons with 15 or more adenomatous colorectal polyps

Persons with multiple hamartomatous or juvenile GI polyps

Persons with a family history of a known hereditary cancer syndrome

CRC Risk ManagementCRC Risk Management

Average Risk

1 No family history CRC OR2 One 2nd or 3rd degree relative with CRC

FOBT annually + flex sig every 5 years OR Colonoscopy every 10 years OR DCBE every 5 years

Age to Begin50 years

CRC Risk ManagementCRC Risk ManagementModerateFamily history Two 1st degree relatives with CRC any age

or one 1st degree relative with CRC lt 60- Colonoscopy every 5 yrs

One 1st degree relative with CRC gt60 or two 2nd degree relatives with CRC any age- Average risk screening

Or 5-10 yrs earlier than earliest case in family

Age to begin

40 years

40 years

CRC Risk ManagementCRC Risk Management

Age to Begin

HNPCC or suspected HNPCC 20-25 years 1 Colonoscopy every 1-2 yrs

2 Genetic counseling consider genetic testing

FAP or suspected FAP 10-12 years 1 Flex sig or colonoscopy every1-2 yrs

2 Genetic counseling consider genetic testing

Case 1 JoanCase 1 Joan Joan age 38 was recently diagnosed with

endometrial cancer Family history reveals

1 Paternal grandmother endometrial cancer age 50 2 Paternal uncle colon cancer age 48 3 Father colonoscopy at age 50 four adenomatous

polyps removed 4 No other significant history 5 Both sides of the family are Northern European

Caucasian

Pedigree Case 1Pedigree Case 1French Irish Scottish German English

88 yr

61 yr 63 yr

4 polyps

50 yrs 38 yr

35 yrDx 38

8 yr10 yr

CRC Dx 48

Dx 50

KEYKEY

Endometrial CA

Colorectal CA

Adenomatous Polyps

Case 1 AssessmentCase 1 Assessment Joan meets Amsterdam II Criteria and is at risk for HNPCC

Refer to genetics for cancer genetic counseling and discussion of genetic testing for HNPCC

Testing options

1 Direct gene testing of MLH1 and MSH2 OR

2 MSIIHC screening of tumor tissue with gene sequencing if MSI positive

Case 2 TedCase 2 Ted Ted is 30 and wants a colonoscopy because his mother

was just diagnosed with colon cancer after routine screening at age 54 Family history reveals

1 Paternal grandfather died of CRC at age 79

2 No hx of endometrial ovarian small bowel or ureterkidney cancer on either side of family

3 Two maternal aunts cervical cancer at ages 30 amp 34

4 Maternal grandmother breast cancer age 85

Pedigree Case 2Pedigree Case 2Italian Irish German

KEY

CRC

Breast CA

Cervical CA

84

d 58 MIBrCa 85 yrs

d87

55 58 60

Colon CA 54 yrs

Cervical CA 30 yrs

Cervical CA 32 yrs

34 yrs 30 yrs

CRC 79 d82

56

Case 2 TedCase 2 Ted Verify Diagnoses Obtain and review pathology reports on

all reported cancers whenever possible

If diagnoses are correct Ted has no family history indicative of a known colon cancer syndrome (HNPCC FAP other)

Tedrsquos lifetime risk of colorectal CA is increased 2 to 3 fold due to one affected first degree relative (gt50)

Moderatefamilial risk Screening by colonoscopy starting at age 40 or 10 yrs earlier than earliest case in family is reasonable

Chemo PreventionChemo Prevention Evidence that ASA NSAIDs Calcium and COX-2

inhibitors may reduce incidence of CA by reducing ofadenomas

1048707 40-50 risk reduction for developing colorectal CA regardless of location in colon age gender and race

Generally performed by RCTrsquos in patients with priorcolorectal CA followed for recurrence of adenomas

Diet fiber and antioxidant vitamins have not beenshown by RCTrsquos to decrease risk of recurrent adenomas

COX-2irsquos and Sulindac have been shown to reduce thenumber of adenomas found in FAP alone

1048707 Not effective for sporadic colon CA 1048707 Actually can cause regression of adenomas

Attenuated FAPAttenuated FAP 20 to 100 polyps usually more proximal

Onset later than FAP average AOO = 50 Lifetime risk of CRC = 80

Extracolonic tumors occur at same rate as FAP Variant of FAP mutations in same APC gene Surveillance

annual colonoscopy starting late teens or early 20rsquos Option of subtotal colectomy

Genetic Testing FAPAFAPGenetic Testing FAPAFAP Test an affected family member first

After genetic counseling and informed consent

APC gene testing can confirm a suspected diagnosis

Family members of a person with a known APC mutation can have mutation-specific testing

Genetic testing for children at risk for FAP can be considered before beginning colon screening

APC gene mutation inAPC gene mutation inAshkenazi JewsAshkenazi Jews

Missense mutation (I1307K) associated with increased risk of CRC and adenomas in Ashkenazi Jews (AJ)

Found in 6 of the general AJ population

12 of AJs with CRC

29 of AJs with CRC and a positive family history

Lifetime risk of CRC in mutation carrier is 10-20

Screening colonoscopy every 2-5 yrs starting at 35 yrs

MAP syndromeMYH geneMAP syndromeMYH gene Multiple adenomatous polyposis (MAP) syndrome

Autosomal recessive mutations in the MYH gene Median number of polyps = 55 Mean age of polyp diagnosis = 30-50 years Polyps mainly small mildly dysplastic tubular adenomas Some

tubulovillous hyperplastic serrated adenomas microadenomas

30 of individuals with 15-100 polyps have homozygous mutations in the MYH gene

Genetic testing should be offered if gt15 polyps (and APC gene testing negative)

Peutz-Jeghers SyndromePeutz-Jeghers Syndrome lt1 of all CRC cases Hamartomatous polyps of GI tract as early as 1st decade Mucocutaneous hyper pigmentation

lips mouth buccal mucosa fingers Usually seen in children lt 5 yrs

Cancer risk colon small intestine stomach pancreas breast ovaries uterus testes

lungs kidneys Mutations in STK11 gene

found in 70 of familial cases and 30-70 of sporadic cases

Familial Juvenile PolyposisFamilial Juvenile Polyposis

lt1 of all CRC cases

Autosomal dominant

5 or more juvenile polyps in colon or GI tract

Appear in 1st or 2nd decade

50 lifetime risk of CRC AOO in 30rsquos

Increased risk gastric GI pancreatic CA

~50 of cases have mutations in either the MADH4 or BMPR1A genes

Family Health HistoryFamily Health History

ldquoThe family tree has become the most important genetic test of all The more you know the more tools you have to practice preventive medicinerdquo

Donna Russo Certified Genetic Counselor NY Presbyterian-Columbia Hospital

Goal ClassificationGoal ClassificationAssessment Risk Classification Intervention

Family History

Average

Moderate

(ldquoFamilialrdquo)

HighGenetic

Personalized prevention recommendations

Standard prevention recommendations

Referral for genetic evaluation with personalized prevention recommendations

Consider Genetics Referral forConsider Genetics Referral for

Two or more family members with CRC at least one lt50

Three or more family members wCRC any age

Patient with colon cancer before 40 yrs

Endometrial cancer and family history of CRC lt50

Persons with more than one primary CRC lt50 yrs or with both endometrial CA and CRC

Family or personal history of CRC and one or more 1st degree relative with an HNPCC-related cancer one diagnosed lt50 yrs

Same side of family

Consider Genetics Referral forConsider Genetics Referral for

MSI andor IHC tumor results suspicious for HNPCC

Autosomal dominant pattern of cancers in the family

Persons with 15 or more adenomatous colorectal polyps

Persons with multiple hamartomatous or juvenile GI polyps

Persons with a family history of a known hereditary cancer syndrome

CRC Risk ManagementCRC Risk Management

Average Risk

1 No family history CRC OR2 One 2nd or 3rd degree relative with CRC

FOBT annually + flex sig every 5 years OR Colonoscopy every 10 years OR DCBE every 5 years

Age to Begin50 years

CRC Risk ManagementCRC Risk ManagementModerateFamily history Two 1st degree relatives with CRC any age

or one 1st degree relative with CRC lt 60- Colonoscopy every 5 yrs

One 1st degree relative with CRC gt60 or two 2nd degree relatives with CRC any age- Average risk screening

Or 5-10 yrs earlier than earliest case in family

Age to begin

40 years

40 years

CRC Risk ManagementCRC Risk Management

Age to Begin

HNPCC or suspected HNPCC 20-25 years 1 Colonoscopy every 1-2 yrs

2 Genetic counseling consider genetic testing

FAP or suspected FAP 10-12 years 1 Flex sig or colonoscopy every1-2 yrs

2 Genetic counseling consider genetic testing

Case 1 JoanCase 1 Joan Joan age 38 was recently diagnosed with

endometrial cancer Family history reveals

1 Paternal grandmother endometrial cancer age 50 2 Paternal uncle colon cancer age 48 3 Father colonoscopy at age 50 four adenomatous

polyps removed 4 No other significant history 5 Both sides of the family are Northern European

Caucasian

Pedigree Case 1Pedigree Case 1French Irish Scottish German English

88 yr

61 yr 63 yr

4 polyps

50 yrs 38 yr

35 yrDx 38

8 yr10 yr

CRC Dx 48

Dx 50

KEYKEY

Endometrial CA

Colorectal CA

Adenomatous Polyps

Case 1 AssessmentCase 1 Assessment Joan meets Amsterdam II Criteria and is at risk for HNPCC

Refer to genetics for cancer genetic counseling and discussion of genetic testing for HNPCC

Testing options

1 Direct gene testing of MLH1 and MSH2 OR

2 MSIIHC screening of tumor tissue with gene sequencing if MSI positive

Case 2 TedCase 2 Ted Ted is 30 and wants a colonoscopy because his mother

was just diagnosed with colon cancer after routine screening at age 54 Family history reveals

1 Paternal grandfather died of CRC at age 79

2 No hx of endometrial ovarian small bowel or ureterkidney cancer on either side of family

3 Two maternal aunts cervical cancer at ages 30 amp 34

4 Maternal grandmother breast cancer age 85

Pedigree Case 2Pedigree Case 2Italian Irish German

KEY

CRC

Breast CA

Cervical CA

84

d 58 MIBrCa 85 yrs

d87

55 58 60

Colon CA 54 yrs

Cervical CA 30 yrs

Cervical CA 32 yrs

34 yrs 30 yrs

CRC 79 d82

56

Case 2 TedCase 2 Ted Verify Diagnoses Obtain and review pathology reports on

all reported cancers whenever possible

If diagnoses are correct Ted has no family history indicative of a known colon cancer syndrome (HNPCC FAP other)

Tedrsquos lifetime risk of colorectal CA is increased 2 to 3 fold due to one affected first degree relative (gt50)

Moderatefamilial risk Screening by colonoscopy starting at age 40 or 10 yrs earlier than earliest case in family is reasonable

Chemo PreventionChemo Prevention Evidence that ASA NSAIDs Calcium and COX-2

inhibitors may reduce incidence of CA by reducing ofadenomas

1048707 40-50 risk reduction for developing colorectal CA regardless of location in colon age gender and race

Generally performed by RCTrsquos in patients with priorcolorectal CA followed for recurrence of adenomas

Diet fiber and antioxidant vitamins have not beenshown by RCTrsquos to decrease risk of recurrent adenomas

COX-2irsquos and Sulindac have been shown to reduce thenumber of adenomas found in FAP alone

1048707 Not effective for sporadic colon CA 1048707 Actually can cause regression of adenomas

Genetic Testing FAPAFAPGenetic Testing FAPAFAP Test an affected family member first

After genetic counseling and informed consent

APC gene testing can confirm a suspected diagnosis

Family members of a person with a known APC mutation can have mutation-specific testing

Genetic testing for children at risk for FAP can be considered before beginning colon screening

APC gene mutation inAPC gene mutation inAshkenazi JewsAshkenazi Jews

Missense mutation (I1307K) associated with increased risk of CRC and adenomas in Ashkenazi Jews (AJ)

Found in 6 of the general AJ population

12 of AJs with CRC

29 of AJs with CRC and a positive family history

Lifetime risk of CRC in mutation carrier is 10-20

Screening colonoscopy every 2-5 yrs starting at 35 yrs

MAP syndromeMYH geneMAP syndromeMYH gene Multiple adenomatous polyposis (MAP) syndrome

Autosomal recessive mutations in the MYH gene Median number of polyps = 55 Mean age of polyp diagnosis = 30-50 years Polyps mainly small mildly dysplastic tubular adenomas Some

tubulovillous hyperplastic serrated adenomas microadenomas

30 of individuals with 15-100 polyps have homozygous mutations in the MYH gene

Genetic testing should be offered if gt15 polyps (and APC gene testing negative)

Peutz-Jeghers SyndromePeutz-Jeghers Syndrome lt1 of all CRC cases Hamartomatous polyps of GI tract as early as 1st decade Mucocutaneous hyper pigmentation

lips mouth buccal mucosa fingers Usually seen in children lt 5 yrs

Cancer risk colon small intestine stomach pancreas breast ovaries uterus testes

lungs kidneys Mutations in STK11 gene

found in 70 of familial cases and 30-70 of sporadic cases

Familial Juvenile PolyposisFamilial Juvenile Polyposis

lt1 of all CRC cases

Autosomal dominant

5 or more juvenile polyps in colon or GI tract

Appear in 1st or 2nd decade

50 lifetime risk of CRC AOO in 30rsquos

Increased risk gastric GI pancreatic CA

~50 of cases have mutations in either the MADH4 or BMPR1A genes

Family Health HistoryFamily Health History

ldquoThe family tree has become the most important genetic test of all The more you know the more tools you have to practice preventive medicinerdquo

Donna Russo Certified Genetic Counselor NY Presbyterian-Columbia Hospital

Goal ClassificationGoal ClassificationAssessment Risk Classification Intervention

Family History

Average

Moderate

(ldquoFamilialrdquo)

HighGenetic

Personalized prevention recommendations

Standard prevention recommendations

Referral for genetic evaluation with personalized prevention recommendations

Consider Genetics Referral forConsider Genetics Referral for

Two or more family members with CRC at least one lt50

Three or more family members wCRC any age

Patient with colon cancer before 40 yrs

Endometrial cancer and family history of CRC lt50

Persons with more than one primary CRC lt50 yrs or with both endometrial CA and CRC

Family or personal history of CRC and one or more 1st degree relative with an HNPCC-related cancer one diagnosed lt50 yrs

Same side of family

Consider Genetics Referral forConsider Genetics Referral for

MSI andor IHC tumor results suspicious for HNPCC

Autosomal dominant pattern of cancers in the family

Persons with 15 or more adenomatous colorectal polyps

Persons with multiple hamartomatous or juvenile GI polyps

Persons with a family history of a known hereditary cancer syndrome

CRC Risk ManagementCRC Risk Management

Average Risk

1 No family history CRC OR2 One 2nd or 3rd degree relative with CRC

FOBT annually + flex sig every 5 years OR Colonoscopy every 10 years OR DCBE every 5 years

Age to Begin50 years

CRC Risk ManagementCRC Risk ManagementModerateFamily history Two 1st degree relatives with CRC any age

or one 1st degree relative with CRC lt 60- Colonoscopy every 5 yrs

One 1st degree relative with CRC gt60 or two 2nd degree relatives with CRC any age- Average risk screening

Or 5-10 yrs earlier than earliest case in family

Age to begin

40 years

40 years

CRC Risk ManagementCRC Risk Management

Age to Begin

HNPCC or suspected HNPCC 20-25 years 1 Colonoscopy every 1-2 yrs

2 Genetic counseling consider genetic testing

FAP or suspected FAP 10-12 years 1 Flex sig or colonoscopy every1-2 yrs

2 Genetic counseling consider genetic testing

Case 1 JoanCase 1 Joan Joan age 38 was recently diagnosed with

endometrial cancer Family history reveals

1 Paternal grandmother endometrial cancer age 50 2 Paternal uncle colon cancer age 48 3 Father colonoscopy at age 50 four adenomatous

polyps removed 4 No other significant history 5 Both sides of the family are Northern European

Caucasian

Pedigree Case 1Pedigree Case 1French Irish Scottish German English

88 yr

61 yr 63 yr

4 polyps

50 yrs 38 yr

35 yrDx 38

8 yr10 yr

CRC Dx 48

Dx 50

KEYKEY

Endometrial CA

Colorectal CA

Adenomatous Polyps

Case 1 AssessmentCase 1 Assessment Joan meets Amsterdam II Criteria and is at risk for HNPCC

Refer to genetics for cancer genetic counseling and discussion of genetic testing for HNPCC

Testing options

1 Direct gene testing of MLH1 and MSH2 OR

2 MSIIHC screening of tumor tissue with gene sequencing if MSI positive

Case 2 TedCase 2 Ted Ted is 30 and wants a colonoscopy because his mother

was just diagnosed with colon cancer after routine screening at age 54 Family history reveals

1 Paternal grandfather died of CRC at age 79

2 No hx of endometrial ovarian small bowel or ureterkidney cancer on either side of family

3 Two maternal aunts cervical cancer at ages 30 amp 34

4 Maternal grandmother breast cancer age 85

Pedigree Case 2Pedigree Case 2Italian Irish German

KEY

CRC

Breast CA

Cervical CA

84

d 58 MIBrCa 85 yrs

d87

55 58 60

Colon CA 54 yrs

Cervical CA 30 yrs

Cervical CA 32 yrs

34 yrs 30 yrs

CRC 79 d82

56

Case 2 TedCase 2 Ted Verify Diagnoses Obtain and review pathology reports on

all reported cancers whenever possible

If diagnoses are correct Ted has no family history indicative of a known colon cancer syndrome (HNPCC FAP other)

Tedrsquos lifetime risk of colorectal CA is increased 2 to 3 fold due to one affected first degree relative (gt50)

Moderatefamilial risk Screening by colonoscopy starting at age 40 or 10 yrs earlier than earliest case in family is reasonable

Chemo PreventionChemo Prevention Evidence that ASA NSAIDs Calcium and COX-2

inhibitors may reduce incidence of CA by reducing ofadenomas

1048707 40-50 risk reduction for developing colorectal CA regardless of location in colon age gender and race

Generally performed by RCTrsquos in patients with priorcolorectal CA followed for recurrence of adenomas

Diet fiber and antioxidant vitamins have not beenshown by RCTrsquos to decrease risk of recurrent adenomas

COX-2irsquos and Sulindac have been shown to reduce thenumber of adenomas found in FAP alone

1048707 Not effective for sporadic colon CA 1048707 Actually can cause regression of adenomas

APC gene mutation inAPC gene mutation inAshkenazi JewsAshkenazi Jews

Missense mutation (I1307K) associated with increased risk of CRC and adenomas in Ashkenazi Jews (AJ)

Found in 6 of the general AJ population

12 of AJs with CRC

29 of AJs with CRC and a positive family history

Lifetime risk of CRC in mutation carrier is 10-20

Screening colonoscopy every 2-5 yrs starting at 35 yrs

MAP syndromeMYH geneMAP syndromeMYH gene Multiple adenomatous polyposis (MAP) syndrome

Autosomal recessive mutations in the MYH gene Median number of polyps = 55 Mean age of polyp diagnosis = 30-50 years Polyps mainly small mildly dysplastic tubular adenomas Some

tubulovillous hyperplastic serrated adenomas microadenomas

30 of individuals with 15-100 polyps have homozygous mutations in the MYH gene

Genetic testing should be offered if gt15 polyps (and APC gene testing negative)

Peutz-Jeghers SyndromePeutz-Jeghers Syndrome lt1 of all CRC cases Hamartomatous polyps of GI tract as early as 1st decade Mucocutaneous hyper pigmentation

lips mouth buccal mucosa fingers Usually seen in children lt 5 yrs

Cancer risk colon small intestine stomach pancreas breast ovaries uterus testes

lungs kidneys Mutations in STK11 gene

found in 70 of familial cases and 30-70 of sporadic cases

Familial Juvenile PolyposisFamilial Juvenile Polyposis

lt1 of all CRC cases

Autosomal dominant

5 or more juvenile polyps in colon or GI tract

Appear in 1st or 2nd decade

50 lifetime risk of CRC AOO in 30rsquos

Increased risk gastric GI pancreatic CA

~50 of cases have mutations in either the MADH4 or BMPR1A genes

Family Health HistoryFamily Health History

ldquoThe family tree has become the most important genetic test of all The more you know the more tools you have to practice preventive medicinerdquo

Donna Russo Certified Genetic Counselor NY Presbyterian-Columbia Hospital

Goal ClassificationGoal ClassificationAssessment Risk Classification Intervention

Family History

Average

Moderate

(ldquoFamilialrdquo)

HighGenetic

Personalized prevention recommendations

Standard prevention recommendations

Referral for genetic evaluation with personalized prevention recommendations

Consider Genetics Referral forConsider Genetics Referral for

Two or more family members with CRC at least one lt50

Three or more family members wCRC any age

Patient with colon cancer before 40 yrs

Endometrial cancer and family history of CRC lt50

Persons with more than one primary CRC lt50 yrs or with both endometrial CA and CRC

Family or personal history of CRC and one or more 1st degree relative with an HNPCC-related cancer one diagnosed lt50 yrs

Same side of family

Consider Genetics Referral forConsider Genetics Referral for

MSI andor IHC tumor results suspicious for HNPCC

Autosomal dominant pattern of cancers in the family

Persons with 15 or more adenomatous colorectal polyps

Persons with multiple hamartomatous or juvenile GI polyps

Persons with a family history of a known hereditary cancer syndrome

CRC Risk ManagementCRC Risk Management

Average Risk

1 No family history CRC OR2 One 2nd or 3rd degree relative with CRC

FOBT annually + flex sig every 5 years OR Colonoscopy every 10 years OR DCBE every 5 years

Age to Begin50 years

CRC Risk ManagementCRC Risk ManagementModerateFamily history Two 1st degree relatives with CRC any age

or one 1st degree relative with CRC lt 60- Colonoscopy every 5 yrs

One 1st degree relative with CRC gt60 or two 2nd degree relatives with CRC any age- Average risk screening

Or 5-10 yrs earlier than earliest case in family

Age to begin

40 years

40 years

CRC Risk ManagementCRC Risk Management

Age to Begin

HNPCC or suspected HNPCC 20-25 years 1 Colonoscopy every 1-2 yrs

2 Genetic counseling consider genetic testing

FAP or suspected FAP 10-12 years 1 Flex sig or colonoscopy every1-2 yrs

2 Genetic counseling consider genetic testing

Case 1 JoanCase 1 Joan Joan age 38 was recently diagnosed with

endometrial cancer Family history reveals

1 Paternal grandmother endometrial cancer age 50 2 Paternal uncle colon cancer age 48 3 Father colonoscopy at age 50 four adenomatous

polyps removed 4 No other significant history 5 Both sides of the family are Northern European

Caucasian

Pedigree Case 1Pedigree Case 1French Irish Scottish German English

88 yr

61 yr 63 yr

4 polyps

50 yrs 38 yr

35 yrDx 38

8 yr10 yr

CRC Dx 48

Dx 50

KEYKEY

Endometrial CA

Colorectal CA

Adenomatous Polyps

Case 1 AssessmentCase 1 Assessment Joan meets Amsterdam II Criteria and is at risk for HNPCC

Refer to genetics for cancer genetic counseling and discussion of genetic testing for HNPCC

Testing options

1 Direct gene testing of MLH1 and MSH2 OR

2 MSIIHC screening of tumor tissue with gene sequencing if MSI positive

Case 2 TedCase 2 Ted Ted is 30 and wants a colonoscopy because his mother

was just diagnosed with colon cancer after routine screening at age 54 Family history reveals

1 Paternal grandfather died of CRC at age 79

2 No hx of endometrial ovarian small bowel or ureterkidney cancer on either side of family

3 Two maternal aunts cervical cancer at ages 30 amp 34

4 Maternal grandmother breast cancer age 85

Pedigree Case 2Pedigree Case 2Italian Irish German

KEY

CRC

Breast CA

Cervical CA

84

d 58 MIBrCa 85 yrs

d87

55 58 60

Colon CA 54 yrs

Cervical CA 30 yrs

Cervical CA 32 yrs

34 yrs 30 yrs

CRC 79 d82

56

Case 2 TedCase 2 Ted Verify Diagnoses Obtain and review pathology reports on

all reported cancers whenever possible

If diagnoses are correct Ted has no family history indicative of a known colon cancer syndrome (HNPCC FAP other)

Tedrsquos lifetime risk of colorectal CA is increased 2 to 3 fold due to one affected first degree relative (gt50)

Moderatefamilial risk Screening by colonoscopy starting at age 40 or 10 yrs earlier than earliest case in family is reasonable

Chemo PreventionChemo Prevention Evidence that ASA NSAIDs Calcium and COX-2

inhibitors may reduce incidence of CA by reducing ofadenomas

1048707 40-50 risk reduction for developing colorectal CA regardless of location in colon age gender and race

Generally performed by RCTrsquos in patients with priorcolorectal CA followed for recurrence of adenomas

Diet fiber and antioxidant vitamins have not beenshown by RCTrsquos to decrease risk of recurrent adenomas

COX-2irsquos and Sulindac have been shown to reduce thenumber of adenomas found in FAP alone

1048707 Not effective for sporadic colon CA 1048707 Actually can cause regression of adenomas

MAP syndromeMYH geneMAP syndromeMYH gene Multiple adenomatous polyposis (MAP) syndrome

Autosomal recessive mutations in the MYH gene Median number of polyps = 55 Mean age of polyp diagnosis = 30-50 years Polyps mainly small mildly dysplastic tubular adenomas Some

tubulovillous hyperplastic serrated adenomas microadenomas

30 of individuals with 15-100 polyps have homozygous mutations in the MYH gene

Genetic testing should be offered if gt15 polyps (and APC gene testing negative)

Peutz-Jeghers SyndromePeutz-Jeghers Syndrome lt1 of all CRC cases Hamartomatous polyps of GI tract as early as 1st decade Mucocutaneous hyper pigmentation

lips mouth buccal mucosa fingers Usually seen in children lt 5 yrs

Cancer risk colon small intestine stomach pancreas breast ovaries uterus testes

lungs kidneys Mutations in STK11 gene

found in 70 of familial cases and 30-70 of sporadic cases

Familial Juvenile PolyposisFamilial Juvenile Polyposis

lt1 of all CRC cases

Autosomal dominant

5 or more juvenile polyps in colon or GI tract

Appear in 1st or 2nd decade

50 lifetime risk of CRC AOO in 30rsquos

Increased risk gastric GI pancreatic CA

~50 of cases have mutations in either the MADH4 or BMPR1A genes

Family Health HistoryFamily Health History

ldquoThe family tree has become the most important genetic test of all The more you know the more tools you have to practice preventive medicinerdquo

Donna Russo Certified Genetic Counselor NY Presbyterian-Columbia Hospital

Goal ClassificationGoal ClassificationAssessment Risk Classification Intervention

Family History

Average

Moderate

(ldquoFamilialrdquo)

HighGenetic

Personalized prevention recommendations

Standard prevention recommendations

Referral for genetic evaluation with personalized prevention recommendations

Consider Genetics Referral forConsider Genetics Referral for

Two or more family members with CRC at least one lt50

Three or more family members wCRC any age

Patient with colon cancer before 40 yrs

Endometrial cancer and family history of CRC lt50

Persons with more than one primary CRC lt50 yrs or with both endometrial CA and CRC

Family or personal history of CRC and one or more 1st degree relative with an HNPCC-related cancer one diagnosed lt50 yrs

Same side of family

Consider Genetics Referral forConsider Genetics Referral for

MSI andor IHC tumor results suspicious for HNPCC

Autosomal dominant pattern of cancers in the family

Persons with 15 or more adenomatous colorectal polyps

Persons with multiple hamartomatous or juvenile GI polyps

Persons with a family history of a known hereditary cancer syndrome

CRC Risk ManagementCRC Risk Management

Average Risk

1 No family history CRC OR2 One 2nd or 3rd degree relative with CRC

FOBT annually + flex sig every 5 years OR Colonoscopy every 10 years OR DCBE every 5 years

Age to Begin50 years

CRC Risk ManagementCRC Risk ManagementModerateFamily history Two 1st degree relatives with CRC any age

or one 1st degree relative with CRC lt 60- Colonoscopy every 5 yrs

One 1st degree relative with CRC gt60 or two 2nd degree relatives with CRC any age- Average risk screening

Or 5-10 yrs earlier than earliest case in family

Age to begin

40 years

40 years

CRC Risk ManagementCRC Risk Management

Age to Begin

HNPCC or suspected HNPCC 20-25 years 1 Colonoscopy every 1-2 yrs

2 Genetic counseling consider genetic testing

FAP or suspected FAP 10-12 years 1 Flex sig or colonoscopy every1-2 yrs

2 Genetic counseling consider genetic testing

Case 1 JoanCase 1 Joan Joan age 38 was recently diagnosed with

endometrial cancer Family history reveals

1 Paternal grandmother endometrial cancer age 50 2 Paternal uncle colon cancer age 48 3 Father colonoscopy at age 50 four adenomatous

polyps removed 4 No other significant history 5 Both sides of the family are Northern European

Caucasian

Pedigree Case 1Pedigree Case 1French Irish Scottish German English

88 yr

61 yr 63 yr

4 polyps

50 yrs 38 yr

35 yrDx 38

8 yr10 yr

CRC Dx 48

Dx 50

KEYKEY

Endometrial CA

Colorectal CA

Adenomatous Polyps

Case 1 AssessmentCase 1 Assessment Joan meets Amsterdam II Criteria and is at risk for HNPCC

Refer to genetics for cancer genetic counseling and discussion of genetic testing for HNPCC

Testing options

1 Direct gene testing of MLH1 and MSH2 OR

2 MSIIHC screening of tumor tissue with gene sequencing if MSI positive

Case 2 TedCase 2 Ted Ted is 30 and wants a colonoscopy because his mother

was just diagnosed with colon cancer after routine screening at age 54 Family history reveals

1 Paternal grandfather died of CRC at age 79

2 No hx of endometrial ovarian small bowel or ureterkidney cancer on either side of family

3 Two maternal aunts cervical cancer at ages 30 amp 34

4 Maternal grandmother breast cancer age 85

Pedigree Case 2Pedigree Case 2Italian Irish German

KEY

CRC

Breast CA

Cervical CA

84

d 58 MIBrCa 85 yrs

d87

55 58 60

Colon CA 54 yrs

Cervical CA 30 yrs

Cervical CA 32 yrs

34 yrs 30 yrs

CRC 79 d82

56

Case 2 TedCase 2 Ted Verify Diagnoses Obtain and review pathology reports on

all reported cancers whenever possible

If diagnoses are correct Ted has no family history indicative of a known colon cancer syndrome (HNPCC FAP other)

Tedrsquos lifetime risk of colorectal CA is increased 2 to 3 fold due to one affected first degree relative (gt50)

Moderatefamilial risk Screening by colonoscopy starting at age 40 or 10 yrs earlier than earliest case in family is reasonable

Chemo PreventionChemo Prevention Evidence that ASA NSAIDs Calcium and COX-2

inhibitors may reduce incidence of CA by reducing ofadenomas

1048707 40-50 risk reduction for developing colorectal CA regardless of location in colon age gender and race

Generally performed by RCTrsquos in patients with priorcolorectal CA followed for recurrence of adenomas

Diet fiber and antioxidant vitamins have not beenshown by RCTrsquos to decrease risk of recurrent adenomas

COX-2irsquos and Sulindac have been shown to reduce thenumber of adenomas found in FAP alone

1048707 Not effective for sporadic colon CA 1048707 Actually can cause regression of adenomas

Peutz-Jeghers SyndromePeutz-Jeghers Syndrome lt1 of all CRC cases Hamartomatous polyps of GI tract as early as 1st decade Mucocutaneous hyper pigmentation

lips mouth buccal mucosa fingers Usually seen in children lt 5 yrs

Cancer risk colon small intestine stomach pancreas breast ovaries uterus testes

lungs kidneys Mutations in STK11 gene

found in 70 of familial cases and 30-70 of sporadic cases

Familial Juvenile PolyposisFamilial Juvenile Polyposis

lt1 of all CRC cases

Autosomal dominant

5 or more juvenile polyps in colon or GI tract

Appear in 1st or 2nd decade

50 lifetime risk of CRC AOO in 30rsquos

Increased risk gastric GI pancreatic CA

~50 of cases have mutations in either the MADH4 or BMPR1A genes

Family Health HistoryFamily Health History

ldquoThe family tree has become the most important genetic test of all The more you know the more tools you have to practice preventive medicinerdquo

Donna Russo Certified Genetic Counselor NY Presbyterian-Columbia Hospital

Goal ClassificationGoal ClassificationAssessment Risk Classification Intervention

Family History

Average

Moderate

(ldquoFamilialrdquo)

HighGenetic

Personalized prevention recommendations

Standard prevention recommendations

Referral for genetic evaluation with personalized prevention recommendations

Consider Genetics Referral forConsider Genetics Referral for

Two or more family members with CRC at least one lt50

Three or more family members wCRC any age

Patient with colon cancer before 40 yrs

Endometrial cancer and family history of CRC lt50

Persons with more than one primary CRC lt50 yrs or with both endometrial CA and CRC

Family or personal history of CRC and one or more 1st degree relative with an HNPCC-related cancer one diagnosed lt50 yrs

Same side of family

Consider Genetics Referral forConsider Genetics Referral for

MSI andor IHC tumor results suspicious for HNPCC

Autosomal dominant pattern of cancers in the family

Persons with 15 or more adenomatous colorectal polyps

Persons with multiple hamartomatous or juvenile GI polyps

Persons with a family history of a known hereditary cancer syndrome

CRC Risk ManagementCRC Risk Management

Average Risk

1 No family history CRC OR2 One 2nd or 3rd degree relative with CRC

FOBT annually + flex sig every 5 years OR Colonoscopy every 10 years OR DCBE every 5 years

Age to Begin50 years

CRC Risk ManagementCRC Risk ManagementModerateFamily history Two 1st degree relatives with CRC any age

or one 1st degree relative with CRC lt 60- Colonoscopy every 5 yrs

One 1st degree relative with CRC gt60 or two 2nd degree relatives with CRC any age- Average risk screening

Or 5-10 yrs earlier than earliest case in family

Age to begin

40 years

40 years

CRC Risk ManagementCRC Risk Management

Age to Begin

HNPCC or suspected HNPCC 20-25 years 1 Colonoscopy every 1-2 yrs

2 Genetic counseling consider genetic testing

FAP or suspected FAP 10-12 years 1 Flex sig or colonoscopy every1-2 yrs

2 Genetic counseling consider genetic testing

Case 1 JoanCase 1 Joan Joan age 38 was recently diagnosed with

endometrial cancer Family history reveals

1 Paternal grandmother endometrial cancer age 50 2 Paternal uncle colon cancer age 48 3 Father colonoscopy at age 50 four adenomatous

polyps removed 4 No other significant history 5 Both sides of the family are Northern European

Caucasian

Pedigree Case 1Pedigree Case 1French Irish Scottish German English

88 yr

61 yr 63 yr

4 polyps

50 yrs 38 yr

35 yrDx 38

8 yr10 yr

CRC Dx 48

Dx 50

KEYKEY

Endometrial CA

Colorectal CA

Adenomatous Polyps

Case 1 AssessmentCase 1 Assessment Joan meets Amsterdam II Criteria and is at risk for HNPCC

Refer to genetics for cancer genetic counseling and discussion of genetic testing for HNPCC

Testing options

1 Direct gene testing of MLH1 and MSH2 OR

2 MSIIHC screening of tumor tissue with gene sequencing if MSI positive

Case 2 TedCase 2 Ted Ted is 30 and wants a colonoscopy because his mother

was just diagnosed with colon cancer after routine screening at age 54 Family history reveals

1 Paternal grandfather died of CRC at age 79

2 No hx of endometrial ovarian small bowel or ureterkidney cancer on either side of family

3 Two maternal aunts cervical cancer at ages 30 amp 34

4 Maternal grandmother breast cancer age 85

Pedigree Case 2Pedigree Case 2Italian Irish German

KEY

CRC

Breast CA

Cervical CA

84

d 58 MIBrCa 85 yrs

d87

55 58 60

Colon CA 54 yrs

Cervical CA 30 yrs

Cervical CA 32 yrs

34 yrs 30 yrs

CRC 79 d82

56

Case 2 TedCase 2 Ted Verify Diagnoses Obtain and review pathology reports on

all reported cancers whenever possible

If diagnoses are correct Ted has no family history indicative of a known colon cancer syndrome (HNPCC FAP other)

Tedrsquos lifetime risk of colorectal CA is increased 2 to 3 fold due to one affected first degree relative (gt50)

Moderatefamilial risk Screening by colonoscopy starting at age 40 or 10 yrs earlier than earliest case in family is reasonable

Chemo PreventionChemo Prevention Evidence that ASA NSAIDs Calcium and COX-2

inhibitors may reduce incidence of CA by reducing ofadenomas

1048707 40-50 risk reduction for developing colorectal CA regardless of location in colon age gender and race

Generally performed by RCTrsquos in patients with priorcolorectal CA followed for recurrence of adenomas

Diet fiber and antioxidant vitamins have not beenshown by RCTrsquos to decrease risk of recurrent adenomas

COX-2irsquos and Sulindac have been shown to reduce thenumber of adenomas found in FAP alone

1048707 Not effective for sporadic colon CA 1048707 Actually can cause regression of adenomas

Familial Juvenile PolyposisFamilial Juvenile Polyposis

lt1 of all CRC cases

Autosomal dominant

5 or more juvenile polyps in colon or GI tract

Appear in 1st or 2nd decade

50 lifetime risk of CRC AOO in 30rsquos

Increased risk gastric GI pancreatic CA

~50 of cases have mutations in either the MADH4 or BMPR1A genes

Family Health HistoryFamily Health History

ldquoThe family tree has become the most important genetic test of all The more you know the more tools you have to practice preventive medicinerdquo

Donna Russo Certified Genetic Counselor NY Presbyterian-Columbia Hospital

Goal ClassificationGoal ClassificationAssessment Risk Classification Intervention

Family History

Average

Moderate

(ldquoFamilialrdquo)

HighGenetic

Personalized prevention recommendations

Standard prevention recommendations

Referral for genetic evaluation with personalized prevention recommendations

Consider Genetics Referral forConsider Genetics Referral for

Two or more family members with CRC at least one lt50

Three or more family members wCRC any age

Patient with colon cancer before 40 yrs

Endometrial cancer and family history of CRC lt50

Persons with more than one primary CRC lt50 yrs or with both endometrial CA and CRC

Family or personal history of CRC and one or more 1st degree relative with an HNPCC-related cancer one diagnosed lt50 yrs

Same side of family

Consider Genetics Referral forConsider Genetics Referral for

MSI andor IHC tumor results suspicious for HNPCC

Autosomal dominant pattern of cancers in the family

Persons with 15 or more adenomatous colorectal polyps

Persons with multiple hamartomatous or juvenile GI polyps

Persons with a family history of a known hereditary cancer syndrome

CRC Risk ManagementCRC Risk Management

Average Risk

1 No family history CRC OR2 One 2nd or 3rd degree relative with CRC

FOBT annually + flex sig every 5 years OR Colonoscopy every 10 years OR DCBE every 5 years

Age to Begin50 years

CRC Risk ManagementCRC Risk ManagementModerateFamily history Two 1st degree relatives with CRC any age

or one 1st degree relative with CRC lt 60- Colonoscopy every 5 yrs

One 1st degree relative with CRC gt60 or two 2nd degree relatives with CRC any age- Average risk screening

Or 5-10 yrs earlier than earliest case in family

Age to begin

40 years

40 years

CRC Risk ManagementCRC Risk Management

Age to Begin

HNPCC or suspected HNPCC 20-25 years 1 Colonoscopy every 1-2 yrs

2 Genetic counseling consider genetic testing

FAP or suspected FAP 10-12 years 1 Flex sig or colonoscopy every1-2 yrs

2 Genetic counseling consider genetic testing

Case 1 JoanCase 1 Joan Joan age 38 was recently diagnosed with

endometrial cancer Family history reveals

1 Paternal grandmother endometrial cancer age 50 2 Paternal uncle colon cancer age 48 3 Father colonoscopy at age 50 four adenomatous

polyps removed 4 No other significant history 5 Both sides of the family are Northern European

Caucasian

Pedigree Case 1Pedigree Case 1French Irish Scottish German English

88 yr

61 yr 63 yr

4 polyps

50 yrs 38 yr

35 yrDx 38

8 yr10 yr

CRC Dx 48

Dx 50

KEYKEY

Endometrial CA

Colorectal CA

Adenomatous Polyps

Case 1 AssessmentCase 1 Assessment Joan meets Amsterdam II Criteria and is at risk for HNPCC

Refer to genetics for cancer genetic counseling and discussion of genetic testing for HNPCC

Testing options

1 Direct gene testing of MLH1 and MSH2 OR

2 MSIIHC screening of tumor tissue with gene sequencing if MSI positive

Case 2 TedCase 2 Ted Ted is 30 and wants a colonoscopy because his mother

was just diagnosed with colon cancer after routine screening at age 54 Family history reveals

1 Paternal grandfather died of CRC at age 79

2 No hx of endometrial ovarian small bowel or ureterkidney cancer on either side of family

3 Two maternal aunts cervical cancer at ages 30 amp 34

4 Maternal grandmother breast cancer age 85

Pedigree Case 2Pedigree Case 2Italian Irish German

KEY

CRC

Breast CA

Cervical CA

84

d 58 MIBrCa 85 yrs

d87

55 58 60

Colon CA 54 yrs

Cervical CA 30 yrs

Cervical CA 32 yrs

34 yrs 30 yrs

CRC 79 d82

56

Case 2 TedCase 2 Ted Verify Diagnoses Obtain and review pathology reports on

all reported cancers whenever possible

If diagnoses are correct Ted has no family history indicative of a known colon cancer syndrome (HNPCC FAP other)

Tedrsquos lifetime risk of colorectal CA is increased 2 to 3 fold due to one affected first degree relative (gt50)

Moderatefamilial risk Screening by colonoscopy starting at age 40 or 10 yrs earlier than earliest case in family is reasonable

Chemo PreventionChemo Prevention Evidence that ASA NSAIDs Calcium and COX-2

inhibitors may reduce incidence of CA by reducing ofadenomas

1048707 40-50 risk reduction for developing colorectal CA regardless of location in colon age gender and race

Generally performed by RCTrsquos in patients with priorcolorectal CA followed for recurrence of adenomas

Diet fiber and antioxidant vitamins have not beenshown by RCTrsquos to decrease risk of recurrent adenomas

COX-2irsquos and Sulindac have been shown to reduce thenumber of adenomas found in FAP alone

1048707 Not effective for sporadic colon CA 1048707 Actually can cause regression of adenomas

Family Health HistoryFamily Health History

ldquoThe family tree has become the most important genetic test of all The more you know the more tools you have to practice preventive medicinerdquo

Donna Russo Certified Genetic Counselor NY Presbyterian-Columbia Hospital

Goal ClassificationGoal ClassificationAssessment Risk Classification Intervention

Family History

Average

Moderate

(ldquoFamilialrdquo)

HighGenetic

Personalized prevention recommendations

Standard prevention recommendations

Referral for genetic evaluation with personalized prevention recommendations

Consider Genetics Referral forConsider Genetics Referral for

Two or more family members with CRC at least one lt50

Three or more family members wCRC any age

Patient with colon cancer before 40 yrs

Endometrial cancer and family history of CRC lt50

Persons with more than one primary CRC lt50 yrs or with both endometrial CA and CRC

Family or personal history of CRC and one or more 1st degree relative with an HNPCC-related cancer one diagnosed lt50 yrs

Same side of family

Consider Genetics Referral forConsider Genetics Referral for

MSI andor IHC tumor results suspicious for HNPCC

Autosomal dominant pattern of cancers in the family

Persons with 15 or more adenomatous colorectal polyps

Persons with multiple hamartomatous or juvenile GI polyps

Persons with a family history of a known hereditary cancer syndrome

CRC Risk ManagementCRC Risk Management

Average Risk

1 No family history CRC OR2 One 2nd or 3rd degree relative with CRC

FOBT annually + flex sig every 5 years OR Colonoscopy every 10 years OR DCBE every 5 years

Age to Begin50 years

CRC Risk ManagementCRC Risk ManagementModerateFamily history Two 1st degree relatives with CRC any age

or one 1st degree relative with CRC lt 60- Colonoscopy every 5 yrs

One 1st degree relative with CRC gt60 or two 2nd degree relatives with CRC any age- Average risk screening

Or 5-10 yrs earlier than earliest case in family

Age to begin

40 years

40 years

CRC Risk ManagementCRC Risk Management

Age to Begin

HNPCC or suspected HNPCC 20-25 years 1 Colonoscopy every 1-2 yrs

2 Genetic counseling consider genetic testing

FAP or suspected FAP 10-12 years 1 Flex sig or colonoscopy every1-2 yrs

2 Genetic counseling consider genetic testing

Case 1 JoanCase 1 Joan Joan age 38 was recently diagnosed with

endometrial cancer Family history reveals

1 Paternal grandmother endometrial cancer age 50 2 Paternal uncle colon cancer age 48 3 Father colonoscopy at age 50 four adenomatous

polyps removed 4 No other significant history 5 Both sides of the family are Northern European

Caucasian

Pedigree Case 1Pedigree Case 1French Irish Scottish German English

88 yr

61 yr 63 yr

4 polyps

50 yrs 38 yr

35 yrDx 38

8 yr10 yr

CRC Dx 48

Dx 50

KEYKEY

Endometrial CA

Colorectal CA

Adenomatous Polyps

Case 1 AssessmentCase 1 Assessment Joan meets Amsterdam II Criteria and is at risk for HNPCC

Refer to genetics for cancer genetic counseling and discussion of genetic testing for HNPCC

Testing options

1 Direct gene testing of MLH1 and MSH2 OR

2 MSIIHC screening of tumor tissue with gene sequencing if MSI positive

Case 2 TedCase 2 Ted Ted is 30 and wants a colonoscopy because his mother

was just diagnosed with colon cancer after routine screening at age 54 Family history reveals

1 Paternal grandfather died of CRC at age 79

2 No hx of endometrial ovarian small bowel or ureterkidney cancer on either side of family

3 Two maternal aunts cervical cancer at ages 30 amp 34

4 Maternal grandmother breast cancer age 85

Pedigree Case 2Pedigree Case 2Italian Irish German

KEY

CRC

Breast CA

Cervical CA

84

d 58 MIBrCa 85 yrs

d87

55 58 60

Colon CA 54 yrs

Cervical CA 30 yrs

Cervical CA 32 yrs

34 yrs 30 yrs

CRC 79 d82

56

Case 2 TedCase 2 Ted Verify Diagnoses Obtain and review pathology reports on

all reported cancers whenever possible

If diagnoses are correct Ted has no family history indicative of a known colon cancer syndrome (HNPCC FAP other)

Tedrsquos lifetime risk of colorectal CA is increased 2 to 3 fold due to one affected first degree relative (gt50)

Moderatefamilial risk Screening by colonoscopy starting at age 40 or 10 yrs earlier than earliest case in family is reasonable

Chemo PreventionChemo Prevention Evidence that ASA NSAIDs Calcium and COX-2

inhibitors may reduce incidence of CA by reducing ofadenomas

1048707 40-50 risk reduction for developing colorectal CA regardless of location in colon age gender and race

Generally performed by RCTrsquos in patients with priorcolorectal CA followed for recurrence of adenomas

Diet fiber and antioxidant vitamins have not beenshown by RCTrsquos to decrease risk of recurrent adenomas

COX-2irsquos and Sulindac have been shown to reduce thenumber of adenomas found in FAP alone

1048707 Not effective for sporadic colon CA 1048707 Actually can cause regression of adenomas

Goal ClassificationGoal ClassificationAssessment Risk Classification Intervention

Family History

Average

Moderate

(ldquoFamilialrdquo)

HighGenetic

Personalized prevention recommendations

Standard prevention recommendations

Referral for genetic evaluation with personalized prevention recommendations

Consider Genetics Referral forConsider Genetics Referral for

Two or more family members with CRC at least one lt50

Three or more family members wCRC any age

Patient with colon cancer before 40 yrs

Endometrial cancer and family history of CRC lt50

Persons with more than one primary CRC lt50 yrs or with both endometrial CA and CRC

Family or personal history of CRC and one or more 1st degree relative with an HNPCC-related cancer one diagnosed lt50 yrs

Same side of family

Consider Genetics Referral forConsider Genetics Referral for

MSI andor IHC tumor results suspicious for HNPCC

Autosomal dominant pattern of cancers in the family

Persons with 15 or more adenomatous colorectal polyps

Persons with multiple hamartomatous or juvenile GI polyps

Persons with a family history of a known hereditary cancer syndrome

CRC Risk ManagementCRC Risk Management

Average Risk

1 No family history CRC OR2 One 2nd or 3rd degree relative with CRC

FOBT annually + flex sig every 5 years OR Colonoscopy every 10 years OR DCBE every 5 years

Age to Begin50 years

CRC Risk ManagementCRC Risk ManagementModerateFamily history Two 1st degree relatives with CRC any age

or one 1st degree relative with CRC lt 60- Colonoscopy every 5 yrs

One 1st degree relative with CRC gt60 or two 2nd degree relatives with CRC any age- Average risk screening

Or 5-10 yrs earlier than earliest case in family

Age to begin

40 years

40 years

CRC Risk ManagementCRC Risk Management

Age to Begin

HNPCC or suspected HNPCC 20-25 years 1 Colonoscopy every 1-2 yrs

2 Genetic counseling consider genetic testing

FAP or suspected FAP 10-12 years 1 Flex sig or colonoscopy every1-2 yrs

2 Genetic counseling consider genetic testing

Case 1 JoanCase 1 Joan Joan age 38 was recently diagnosed with

endometrial cancer Family history reveals

1 Paternal grandmother endometrial cancer age 50 2 Paternal uncle colon cancer age 48 3 Father colonoscopy at age 50 four adenomatous

polyps removed 4 No other significant history 5 Both sides of the family are Northern European

Caucasian

Pedigree Case 1Pedigree Case 1French Irish Scottish German English

88 yr

61 yr 63 yr

4 polyps

50 yrs 38 yr

35 yrDx 38

8 yr10 yr

CRC Dx 48

Dx 50

KEYKEY

Endometrial CA

Colorectal CA

Adenomatous Polyps

Case 1 AssessmentCase 1 Assessment Joan meets Amsterdam II Criteria and is at risk for HNPCC

Refer to genetics for cancer genetic counseling and discussion of genetic testing for HNPCC

Testing options

1 Direct gene testing of MLH1 and MSH2 OR

2 MSIIHC screening of tumor tissue with gene sequencing if MSI positive

Case 2 TedCase 2 Ted Ted is 30 and wants a colonoscopy because his mother

was just diagnosed with colon cancer after routine screening at age 54 Family history reveals

1 Paternal grandfather died of CRC at age 79

2 No hx of endometrial ovarian small bowel or ureterkidney cancer on either side of family

3 Two maternal aunts cervical cancer at ages 30 amp 34

4 Maternal grandmother breast cancer age 85

Pedigree Case 2Pedigree Case 2Italian Irish German

KEY

CRC

Breast CA

Cervical CA

84

d 58 MIBrCa 85 yrs

d87

55 58 60

Colon CA 54 yrs

Cervical CA 30 yrs

Cervical CA 32 yrs

34 yrs 30 yrs

CRC 79 d82

56

Case 2 TedCase 2 Ted Verify Diagnoses Obtain and review pathology reports on

all reported cancers whenever possible

If diagnoses are correct Ted has no family history indicative of a known colon cancer syndrome (HNPCC FAP other)

Tedrsquos lifetime risk of colorectal CA is increased 2 to 3 fold due to one affected first degree relative (gt50)

Moderatefamilial risk Screening by colonoscopy starting at age 40 or 10 yrs earlier than earliest case in family is reasonable

Chemo PreventionChemo Prevention Evidence that ASA NSAIDs Calcium and COX-2

inhibitors may reduce incidence of CA by reducing ofadenomas

1048707 40-50 risk reduction for developing colorectal CA regardless of location in colon age gender and race

Generally performed by RCTrsquos in patients with priorcolorectal CA followed for recurrence of adenomas

Diet fiber and antioxidant vitamins have not beenshown by RCTrsquos to decrease risk of recurrent adenomas

COX-2irsquos and Sulindac have been shown to reduce thenumber of adenomas found in FAP alone

1048707 Not effective for sporadic colon CA 1048707 Actually can cause regression of adenomas

Consider Genetics Referral forConsider Genetics Referral for

Two or more family members with CRC at least one lt50

Three or more family members wCRC any age

Patient with colon cancer before 40 yrs

Endometrial cancer and family history of CRC lt50

Persons with more than one primary CRC lt50 yrs or with both endometrial CA and CRC

Family or personal history of CRC and one or more 1st degree relative with an HNPCC-related cancer one diagnosed lt50 yrs

Same side of family

Consider Genetics Referral forConsider Genetics Referral for

MSI andor IHC tumor results suspicious for HNPCC

Autosomal dominant pattern of cancers in the family

Persons with 15 or more adenomatous colorectal polyps

Persons with multiple hamartomatous or juvenile GI polyps

Persons with a family history of a known hereditary cancer syndrome

CRC Risk ManagementCRC Risk Management

Average Risk

1 No family history CRC OR2 One 2nd or 3rd degree relative with CRC

FOBT annually + flex sig every 5 years OR Colonoscopy every 10 years OR DCBE every 5 years

Age to Begin50 years

CRC Risk ManagementCRC Risk ManagementModerateFamily history Two 1st degree relatives with CRC any age

or one 1st degree relative with CRC lt 60- Colonoscopy every 5 yrs

One 1st degree relative with CRC gt60 or two 2nd degree relatives with CRC any age- Average risk screening

Or 5-10 yrs earlier than earliest case in family

Age to begin

40 years

40 years

CRC Risk ManagementCRC Risk Management

Age to Begin

HNPCC or suspected HNPCC 20-25 years 1 Colonoscopy every 1-2 yrs

2 Genetic counseling consider genetic testing

FAP or suspected FAP 10-12 years 1 Flex sig or colonoscopy every1-2 yrs

2 Genetic counseling consider genetic testing

Case 1 JoanCase 1 Joan Joan age 38 was recently diagnosed with

endometrial cancer Family history reveals

1 Paternal grandmother endometrial cancer age 50 2 Paternal uncle colon cancer age 48 3 Father colonoscopy at age 50 four adenomatous

polyps removed 4 No other significant history 5 Both sides of the family are Northern European

Caucasian

Pedigree Case 1Pedigree Case 1French Irish Scottish German English

88 yr

61 yr 63 yr

4 polyps

50 yrs 38 yr

35 yrDx 38

8 yr10 yr

CRC Dx 48

Dx 50

KEYKEY

Endometrial CA

Colorectal CA

Adenomatous Polyps

Case 1 AssessmentCase 1 Assessment Joan meets Amsterdam II Criteria and is at risk for HNPCC

Refer to genetics for cancer genetic counseling and discussion of genetic testing for HNPCC

Testing options

1 Direct gene testing of MLH1 and MSH2 OR

2 MSIIHC screening of tumor tissue with gene sequencing if MSI positive

Case 2 TedCase 2 Ted Ted is 30 and wants a colonoscopy because his mother

was just diagnosed with colon cancer after routine screening at age 54 Family history reveals

1 Paternal grandfather died of CRC at age 79

2 No hx of endometrial ovarian small bowel or ureterkidney cancer on either side of family

3 Two maternal aunts cervical cancer at ages 30 amp 34

4 Maternal grandmother breast cancer age 85

Pedigree Case 2Pedigree Case 2Italian Irish German

KEY

CRC

Breast CA

Cervical CA

84

d 58 MIBrCa 85 yrs

d87

55 58 60

Colon CA 54 yrs

Cervical CA 30 yrs

Cervical CA 32 yrs

34 yrs 30 yrs

CRC 79 d82

56

Case 2 TedCase 2 Ted Verify Diagnoses Obtain and review pathology reports on

all reported cancers whenever possible

If diagnoses are correct Ted has no family history indicative of a known colon cancer syndrome (HNPCC FAP other)

Tedrsquos lifetime risk of colorectal CA is increased 2 to 3 fold due to one affected first degree relative (gt50)

Moderatefamilial risk Screening by colonoscopy starting at age 40 or 10 yrs earlier than earliest case in family is reasonable

Chemo PreventionChemo Prevention Evidence that ASA NSAIDs Calcium and COX-2

inhibitors may reduce incidence of CA by reducing ofadenomas

1048707 40-50 risk reduction for developing colorectal CA regardless of location in colon age gender and race

Generally performed by RCTrsquos in patients with priorcolorectal CA followed for recurrence of adenomas

Diet fiber and antioxidant vitamins have not beenshown by RCTrsquos to decrease risk of recurrent adenomas

COX-2irsquos and Sulindac have been shown to reduce thenumber of adenomas found in FAP alone

1048707 Not effective for sporadic colon CA 1048707 Actually can cause regression of adenomas

Consider Genetics Referral forConsider Genetics Referral for

MSI andor IHC tumor results suspicious for HNPCC

Autosomal dominant pattern of cancers in the family

Persons with 15 or more adenomatous colorectal polyps

Persons with multiple hamartomatous or juvenile GI polyps

Persons with a family history of a known hereditary cancer syndrome

CRC Risk ManagementCRC Risk Management

Average Risk

1 No family history CRC OR2 One 2nd or 3rd degree relative with CRC

FOBT annually + flex sig every 5 years OR Colonoscopy every 10 years OR DCBE every 5 years

Age to Begin50 years

CRC Risk ManagementCRC Risk ManagementModerateFamily history Two 1st degree relatives with CRC any age

or one 1st degree relative with CRC lt 60- Colonoscopy every 5 yrs

One 1st degree relative with CRC gt60 or two 2nd degree relatives with CRC any age- Average risk screening

Or 5-10 yrs earlier than earliest case in family

Age to begin

40 years

40 years

CRC Risk ManagementCRC Risk Management

Age to Begin

HNPCC or suspected HNPCC 20-25 years 1 Colonoscopy every 1-2 yrs

2 Genetic counseling consider genetic testing

FAP or suspected FAP 10-12 years 1 Flex sig or colonoscopy every1-2 yrs

2 Genetic counseling consider genetic testing

Case 1 JoanCase 1 Joan Joan age 38 was recently diagnosed with

endometrial cancer Family history reveals

1 Paternal grandmother endometrial cancer age 50 2 Paternal uncle colon cancer age 48 3 Father colonoscopy at age 50 four adenomatous

polyps removed 4 No other significant history 5 Both sides of the family are Northern European

Caucasian

Pedigree Case 1Pedigree Case 1French Irish Scottish German English

88 yr

61 yr 63 yr

4 polyps

50 yrs 38 yr

35 yrDx 38

8 yr10 yr

CRC Dx 48

Dx 50

KEYKEY

Endometrial CA

Colorectal CA

Adenomatous Polyps

Case 1 AssessmentCase 1 Assessment Joan meets Amsterdam II Criteria and is at risk for HNPCC

Refer to genetics for cancer genetic counseling and discussion of genetic testing for HNPCC

Testing options

1 Direct gene testing of MLH1 and MSH2 OR

2 MSIIHC screening of tumor tissue with gene sequencing if MSI positive

Case 2 TedCase 2 Ted Ted is 30 and wants a colonoscopy because his mother

was just diagnosed with colon cancer after routine screening at age 54 Family history reveals

1 Paternal grandfather died of CRC at age 79

2 No hx of endometrial ovarian small bowel or ureterkidney cancer on either side of family

3 Two maternal aunts cervical cancer at ages 30 amp 34

4 Maternal grandmother breast cancer age 85

Pedigree Case 2Pedigree Case 2Italian Irish German

KEY

CRC

Breast CA

Cervical CA

84

d 58 MIBrCa 85 yrs

d87

55 58 60

Colon CA 54 yrs

Cervical CA 30 yrs

Cervical CA 32 yrs

34 yrs 30 yrs

CRC 79 d82

56

Case 2 TedCase 2 Ted Verify Diagnoses Obtain and review pathology reports on

all reported cancers whenever possible

If diagnoses are correct Ted has no family history indicative of a known colon cancer syndrome (HNPCC FAP other)

Tedrsquos lifetime risk of colorectal CA is increased 2 to 3 fold due to one affected first degree relative (gt50)

Moderatefamilial risk Screening by colonoscopy starting at age 40 or 10 yrs earlier than earliest case in family is reasonable

Chemo PreventionChemo Prevention Evidence that ASA NSAIDs Calcium and COX-2

inhibitors may reduce incidence of CA by reducing ofadenomas

1048707 40-50 risk reduction for developing colorectal CA regardless of location in colon age gender and race

Generally performed by RCTrsquos in patients with priorcolorectal CA followed for recurrence of adenomas

Diet fiber and antioxidant vitamins have not beenshown by RCTrsquos to decrease risk of recurrent adenomas

COX-2irsquos and Sulindac have been shown to reduce thenumber of adenomas found in FAP alone

1048707 Not effective for sporadic colon CA 1048707 Actually can cause regression of adenomas

CRC Risk ManagementCRC Risk Management

Average Risk

1 No family history CRC OR2 One 2nd or 3rd degree relative with CRC

FOBT annually + flex sig every 5 years OR Colonoscopy every 10 years OR DCBE every 5 years

Age to Begin50 years

CRC Risk ManagementCRC Risk ManagementModerateFamily history Two 1st degree relatives with CRC any age

or one 1st degree relative with CRC lt 60- Colonoscopy every 5 yrs

One 1st degree relative with CRC gt60 or two 2nd degree relatives with CRC any age- Average risk screening

Or 5-10 yrs earlier than earliest case in family

Age to begin

40 years

40 years

CRC Risk ManagementCRC Risk Management

Age to Begin

HNPCC or suspected HNPCC 20-25 years 1 Colonoscopy every 1-2 yrs

2 Genetic counseling consider genetic testing

FAP or suspected FAP 10-12 years 1 Flex sig or colonoscopy every1-2 yrs

2 Genetic counseling consider genetic testing

Case 1 JoanCase 1 Joan Joan age 38 was recently diagnosed with

endometrial cancer Family history reveals

1 Paternal grandmother endometrial cancer age 50 2 Paternal uncle colon cancer age 48 3 Father colonoscopy at age 50 four adenomatous

polyps removed 4 No other significant history 5 Both sides of the family are Northern European

Caucasian

Pedigree Case 1Pedigree Case 1French Irish Scottish German English

88 yr

61 yr 63 yr

4 polyps

50 yrs 38 yr

35 yrDx 38

8 yr10 yr

CRC Dx 48

Dx 50

KEYKEY

Endometrial CA

Colorectal CA

Adenomatous Polyps

Case 1 AssessmentCase 1 Assessment Joan meets Amsterdam II Criteria and is at risk for HNPCC

Refer to genetics for cancer genetic counseling and discussion of genetic testing for HNPCC

Testing options

1 Direct gene testing of MLH1 and MSH2 OR

2 MSIIHC screening of tumor tissue with gene sequencing if MSI positive

Case 2 TedCase 2 Ted Ted is 30 and wants a colonoscopy because his mother

was just diagnosed with colon cancer after routine screening at age 54 Family history reveals

1 Paternal grandfather died of CRC at age 79

2 No hx of endometrial ovarian small bowel or ureterkidney cancer on either side of family

3 Two maternal aunts cervical cancer at ages 30 amp 34

4 Maternal grandmother breast cancer age 85

Pedigree Case 2Pedigree Case 2Italian Irish German

KEY

CRC

Breast CA

Cervical CA

84

d 58 MIBrCa 85 yrs

d87

55 58 60

Colon CA 54 yrs

Cervical CA 30 yrs

Cervical CA 32 yrs

34 yrs 30 yrs

CRC 79 d82

56

Case 2 TedCase 2 Ted Verify Diagnoses Obtain and review pathology reports on

all reported cancers whenever possible

If diagnoses are correct Ted has no family history indicative of a known colon cancer syndrome (HNPCC FAP other)

Tedrsquos lifetime risk of colorectal CA is increased 2 to 3 fold due to one affected first degree relative (gt50)

Moderatefamilial risk Screening by colonoscopy starting at age 40 or 10 yrs earlier than earliest case in family is reasonable

Chemo PreventionChemo Prevention Evidence that ASA NSAIDs Calcium and COX-2

inhibitors may reduce incidence of CA by reducing ofadenomas

1048707 40-50 risk reduction for developing colorectal CA regardless of location in colon age gender and race

Generally performed by RCTrsquos in patients with priorcolorectal CA followed for recurrence of adenomas

Diet fiber and antioxidant vitamins have not beenshown by RCTrsquos to decrease risk of recurrent adenomas

COX-2irsquos and Sulindac have been shown to reduce thenumber of adenomas found in FAP alone

1048707 Not effective for sporadic colon CA 1048707 Actually can cause regression of adenomas

CRC Risk ManagementCRC Risk ManagementModerateFamily history Two 1st degree relatives with CRC any age

or one 1st degree relative with CRC lt 60- Colonoscopy every 5 yrs

One 1st degree relative with CRC gt60 or two 2nd degree relatives with CRC any age- Average risk screening

Or 5-10 yrs earlier than earliest case in family

Age to begin

40 years

40 years

CRC Risk ManagementCRC Risk Management

Age to Begin

HNPCC or suspected HNPCC 20-25 years 1 Colonoscopy every 1-2 yrs

2 Genetic counseling consider genetic testing

FAP or suspected FAP 10-12 years 1 Flex sig or colonoscopy every1-2 yrs

2 Genetic counseling consider genetic testing

Case 1 JoanCase 1 Joan Joan age 38 was recently diagnosed with

endometrial cancer Family history reveals

1 Paternal grandmother endometrial cancer age 50 2 Paternal uncle colon cancer age 48 3 Father colonoscopy at age 50 four adenomatous

polyps removed 4 No other significant history 5 Both sides of the family are Northern European

Caucasian

Pedigree Case 1Pedigree Case 1French Irish Scottish German English

88 yr

61 yr 63 yr

4 polyps

50 yrs 38 yr

35 yrDx 38

8 yr10 yr

CRC Dx 48

Dx 50

KEYKEY

Endometrial CA

Colorectal CA

Adenomatous Polyps

Case 1 AssessmentCase 1 Assessment Joan meets Amsterdam II Criteria and is at risk for HNPCC

Refer to genetics for cancer genetic counseling and discussion of genetic testing for HNPCC

Testing options

1 Direct gene testing of MLH1 and MSH2 OR

2 MSIIHC screening of tumor tissue with gene sequencing if MSI positive

Case 2 TedCase 2 Ted Ted is 30 and wants a colonoscopy because his mother

was just diagnosed with colon cancer after routine screening at age 54 Family history reveals

1 Paternal grandfather died of CRC at age 79

2 No hx of endometrial ovarian small bowel or ureterkidney cancer on either side of family

3 Two maternal aunts cervical cancer at ages 30 amp 34

4 Maternal grandmother breast cancer age 85

Pedigree Case 2Pedigree Case 2Italian Irish German

KEY

CRC

Breast CA

Cervical CA

84

d 58 MIBrCa 85 yrs

d87

55 58 60

Colon CA 54 yrs

Cervical CA 30 yrs

Cervical CA 32 yrs

34 yrs 30 yrs

CRC 79 d82

56

Case 2 TedCase 2 Ted Verify Diagnoses Obtain and review pathology reports on

all reported cancers whenever possible

If diagnoses are correct Ted has no family history indicative of a known colon cancer syndrome (HNPCC FAP other)

Tedrsquos lifetime risk of colorectal CA is increased 2 to 3 fold due to one affected first degree relative (gt50)

Moderatefamilial risk Screening by colonoscopy starting at age 40 or 10 yrs earlier than earliest case in family is reasonable

Chemo PreventionChemo Prevention Evidence that ASA NSAIDs Calcium and COX-2

inhibitors may reduce incidence of CA by reducing ofadenomas

1048707 40-50 risk reduction for developing colorectal CA regardless of location in colon age gender and race

Generally performed by RCTrsquos in patients with priorcolorectal CA followed for recurrence of adenomas

Diet fiber and antioxidant vitamins have not beenshown by RCTrsquos to decrease risk of recurrent adenomas

COX-2irsquos and Sulindac have been shown to reduce thenumber of adenomas found in FAP alone

1048707 Not effective for sporadic colon CA 1048707 Actually can cause regression of adenomas

CRC Risk ManagementCRC Risk Management

Age to Begin

HNPCC or suspected HNPCC 20-25 years 1 Colonoscopy every 1-2 yrs

2 Genetic counseling consider genetic testing

FAP or suspected FAP 10-12 years 1 Flex sig or colonoscopy every1-2 yrs

2 Genetic counseling consider genetic testing

Case 1 JoanCase 1 Joan Joan age 38 was recently diagnosed with

endometrial cancer Family history reveals

1 Paternal grandmother endometrial cancer age 50 2 Paternal uncle colon cancer age 48 3 Father colonoscopy at age 50 four adenomatous

polyps removed 4 No other significant history 5 Both sides of the family are Northern European

Caucasian

Pedigree Case 1Pedigree Case 1French Irish Scottish German English

88 yr

61 yr 63 yr

4 polyps

50 yrs 38 yr

35 yrDx 38

8 yr10 yr

CRC Dx 48

Dx 50

KEYKEY

Endometrial CA

Colorectal CA

Adenomatous Polyps

Case 1 AssessmentCase 1 Assessment Joan meets Amsterdam II Criteria and is at risk for HNPCC

Refer to genetics for cancer genetic counseling and discussion of genetic testing for HNPCC

Testing options

1 Direct gene testing of MLH1 and MSH2 OR

2 MSIIHC screening of tumor tissue with gene sequencing if MSI positive

Case 2 TedCase 2 Ted Ted is 30 and wants a colonoscopy because his mother

was just diagnosed with colon cancer after routine screening at age 54 Family history reveals

1 Paternal grandfather died of CRC at age 79

2 No hx of endometrial ovarian small bowel or ureterkidney cancer on either side of family

3 Two maternal aunts cervical cancer at ages 30 amp 34

4 Maternal grandmother breast cancer age 85

Pedigree Case 2Pedigree Case 2Italian Irish German

KEY

CRC

Breast CA

Cervical CA

84

d 58 MIBrCa 85 yrs

d87

55 58 60

Colon CA 54 yrs

Cervical CA 30 yrs

Cervical CA 32 yrs

34 yrs 30 yrs

CRC 79 d82

56

Case 2 TedCase 2 Ted Verify Diagnoses Obtain and review pathology reports on

all reported cancers whenever possible

If diagnoses are correct Ted has no family history indicative of a known colon cancer syndrome (HNPCC FAP other)

Tedrsquos lifetime risk of colorectal CA is increased 2 to 3 fold due to one affected first degree relative (gt50)

Moderatefamilial risk Screening by colonoscopy starting at age 40 or 10 yrs earlier than earliest case in family is reasonable

Chemo PreventionChemo Prevention Evidence that ASA NSAIDs Calcium and COX-2

inhibitors may reduce incidence of CA by reducing ofadenomas

1048707 40-50 risk reduction for developing colorectal CA regardless of location in colon age gender and race

Generally performed by RCTrsquos in patients with priorcolorectal CA followed for recurrence of adenomas

Diet fiber and antioxidant vitamins have not beenshown by RCTrsquos to decrease risk of recurrent adenomas

COX-2irsquos and Sulindac have been shown to reduce thenumber of adenomas found in FAP alone

1048707 Not effective for sporadic colon CA 1048707 Actually can cause regression of adenomas

Case 1 JoanCase 1 Joan Joan age 38 was recently diagnosed with

endometrial cancer Family history reveals

1 Paternal grandmother endometrial cancer age 50 2 Paternal uncle colon cancer age 48 3 Father colonoscopy at age 50 four adenomatous

polyps removed 4 No other significant history 5 Both sides of the family are Northern European

Caucasian

Pedigree Case 1Pedigree Case 1French Irish Scottish German English

88 yr

61 yr 63 yr

4 polyps

50 yrs 38 yr

35 yrDx 38

8 yr10 yr

CRC Dx 48

Dx 50

KEYKEY

Endometrial CA

Colorectal CA

Adenomatous Polyps

Case 1 AssessmentCase 1 Assessment Joan meets Amsterdam II Criteria and is at risk for HNPCC

Refer to genetics for cancer genetic counseling and discussion of genetic testing for HNPCC

Testing options

1 Direct gene testing of MLH1 and MSH2 OR

2 MSIIHC screening of tumor tissue with gene sequencing if MSI positive

Case 2 TedCase 2 Ted Ted is 30 and wants a colonoscopy because his mother

was just diagnosed with colon cancer after routine screening at age 54 Family history reveals

1 Paternal grandfather died of CRC at age 79

2 No hx of endometrial ovarian small bowel or ureterkidney cancer on either side of family

3 Two maternal aunts cervical cancer at ages 30 amp 34

4 Maternal grandmother breast cancer age 85

Pedigree Case 2Pedigree Case 2Italian Irish German

KEY

CRC

Breast CA

Cervical CA

84

d 58 MIBrCa 85 yrs

d87

55 58 60

Colon CA 54 yrs

Cervical CA 30 yrs

Cervical CA 32 yrs

34 yrs 30 yrs

CRC 79 d82

56

Case 2 TedCase 2 Ted Verify Diagnoses Obtain and review pathology reports on

all reported cancers whenever possible

If diagnoses are correct Ted has no family history indicative of a known colon cancer syndrome (HNPCC FAP other)

Tedrsquos lifetime risk of colorectal CA is increased 2 to 3 fold due to one affected first degree relative (gt50)

Moderatefamilial risk Screening by colonoscopy starting at age 40 or 10 yrs earlier than earliest case in family is reasonable

Chemo PreventionChemo Prevention Evidence that ASA NSAIDs Calcium and COX-2

inhibitors may reduce incidence of CA by reducing ofadenomas

1048707 40-50 risk reduction for developing colorectal CA regardless of location in colon age gender and race

Generally performed by RCTrsquos in patients with priorcolorectal CA followed for recurrence of adenomas

Diet fiber and antioxidant vitamins have not beenshown by RCTrsquos to decrease risk of recurrent adenomas

COX-2irsquos and Sulindac have been shown to reduce thenumber of adenomas found in FAP alone

1048707 Not effective for sporadic colon CA 1048707 Actually can cause regression of adenomas

Pedigree Case 1Pedigree Case 1French Irish Scottish German English

88 yr

61 yr 63 yr

4 polyps

50 yrs 38 yr

35 yrDx 38

8 yr10 yr

CRC Dx 48

Dx 50

KEYKEY

Endometrial CA

Colorectal CA

Adenomatous Polyps

Case 1 AssessmentCase 1 Assessment Joan meets Amsterdam II Criteria and is at risk for HNPCC

Refer to genetics for cancer genetic counseling and discussion of genetic testing for HNPCC

Testing options

1 Direct gene testing of MLH1 and MSH2 OR

2 MSIIHC screening of tumor tissue with gene sequencing if MSI positive

Case 2 TedCase 2 Ted Ted is 30 and wants a colonoscopy because his mother

was just diagnosed with colon cancer after routine screening at age 54 Family history reveals

1 Paternal grandfather died of CRC at age 79

2 No hx of endometrial ovarian small bowel or ureterkidney cancer on either side of family

3 Two maternal aunts cervical cancer at ages 30 amp 34

4 Maternal grandmother breast cancer age 85

Pedigree Case 2Pedigree Case 2Italian Irish German

KEY

CRC

Breast CA

Cervical CA

84

d 58 MIBrCa 85 yrs

d87

55 58 60

Colon CA 54 yrs

Cervical CA 30 yrs

Cervical CA 32 yrs

34 yrs 30 yrs

CRC 79 d82

56

Case 2 TedCase 2 Ted Verify Diagnoses Obtain and review pathology reports on

all reported cancers whenever possible

If diagnoses are correct Ted has no family history indicative of a known colon cancer syndrome (HNPCC FAP other)

Tedrsquos lifetime risk of colorectal CA is increased 2 to 3 fold due to one affected first degree relative (gt50)

Moderatefamilial risk Screening by colonoscopy starting at age 40 or 10 yrs earlier than earliest case in family is reasonable

Chemo PreventionChemo Prevention Evidence that ASA NSAIDs Calcium and COX-2

inhibitors may reduce incidence of CA by reducing ofadenomas

1048707 40-50 risk reduction for developing colorectal CA regardless of location in colon age gender and race

Generally performed by RCTrsquos in patients with priorcolorectal CA followed for recurrence of adenomas

Diet fiber and antioxidant vitamins have not beenshown by RCTrsquos to decrease risk of recurrent adenomas

COX-2irsquos and Sulindac have been shown to reduce thenumber of adenomas found in FAP alone

1048707 Not effective for sporadic colon CA 1048707 Actually can cause regression of adenomas

Case 1 AssessmentCase 1 Assessment Joan meets Amsterdam II Criteria and is at risk for HNPCC

Refer to genetics for cancer genetic counseling and discussion of genetic testing for HNPCC

Testing options

1 Direct gene testing of MLH1 and MSH2 OR

2 MSIIHC screening of tumor tissue with gene sequencing if MSI positive

Case 2 TedCase 2 Ted Ted is 30 and wants a colonoscopy because his mother

was just diagnosed with colon cancer after routine screening at age 54 Family history reveals

1 Paternal grandfather died of CRC at age 79

2 No hx of endometrial ovarian small bowel or ureterkidney cancer on either side of family

3 Two maternal aunts cervical cancer at ages 30 amp 34

4 Maternal grandmother breast cancer age 85

Pedigree Case 2Pedigree Case 2Italian Irish German

KEY

CRC

Breast CA

Cervical CA

84

d 58 MIBrCa 85 yrs

d87

55 58 60

Colon CA 54 yrs

Cervical CA 30 yrs

Cervical CA 32 yrs

34 yrs 30 yrs

CRC 79 d82

56

Case 2 TedCase 2 Ted Verify Diagnoses Obtain and review pathology reports on

all reported cancers whenever possible

If diagnoses are correct Ted has no family history indicative of a known colon cancer syndrome (HNPCC FAP other)

Tedrsquos lifetime risk of colorectal CA is increased 2 to 3 fold due to one affected first degree relative (gt50)

Moderatefamilial risk Screening by colonoscopy starting at age 40 or 10 yrs earlier than earliest case in family is reasonable

Chemo PreventionChemo Prevention Evidence that ASA NSAIDs Calcium and COX-2

inhibitors may reduce incidence of CA by reducing ofadenomas

1048707 40-50 risk reduction for developing colorectal CA regardless of location in colon age gender and race

Generally performed by RCTrsquos in patients with priorcolorectal CA followed for recurrence of adenomas

Diet fiber and antioxidant vitamins have not beenshown by RCTrsquos to decrease risk of recurrent adenomas

COX-2irsquos and Sulindac have been shown to reduce thenumber of adenomas found in FAP alone

1048707 Not effective for sporadic colon CA 1048707 Actually can cause regression of adenomas

Case 2 TedCase 2 Ted Ted is 30 and wants a colonoscopy because his mother

was just diagnosed with colon cancer after routine screening at age 54 Family history reveals

1 Paternal grandfather died of CRC at age 79

2 No hx of endometrial ovarian small bowel or ureterkidney cancer on either side of family

3 Two maternal aunts cervical cancer at ages 30 amp 34

4 Maternal grandmother breast cancer age 85

Pedigree Case 2Pedigree Case 2Italian Irish German

KEY

CRC

Breast CA

Cervical CA

84

d 58 MIBrCa 85 yrs

d87

55 58 60

Colon CA 54 yrs

Cervical CA 30 yrs

Cervical CA 32 yrs

34 yrs 30 yrs

CRC 79 d82

56

Case 2 TedCase 2 Ted Verify Diagnoses Obtain and review pathology reports on

all reported cancers whenever possible

If diagnoses are correct Ted has no family history indicative of a known colon cancer syndrome (HNPCC FAP other)

Tedrsquos lifetime risk of colorectal CA is increased 2 to 3 fold due to one affected first degree relative (gt50)

Moderatefamilial risk Screening by colonoscopy starting at age 40 or 10 yrs earlier than earliest case in family is reasonable

Chemo PreventionChemo Prevention Evidence that ASA NSAIDs Calcium and COX-2

inhibitors may reduce incidence of CA by reducing ofadenomas

1048707 40-50 risk reduction for developing colorectal CA regardless of location in colon age gender and race

Generally performed by RCTrsquos in patients with priorcolorectal CA followed for recurrence of adenomas

Diet fiber and antioxidant vitamins have not beenshown by RCTrsquos to decrease risk of recurrent adenomas

COX-2irsquos and Sulindac have been shown to reduce thenumber of adenomas found in FAP alone

1048707 Not effective for sporadic colon CA 1048707 Actually can cause regression of adenomas

Pedigree Case 2Pedigree Case 2Italian Irish German

KEY

CRC

Breast CA

Cervical CA

84

d 58 MIBrCa 85 yrs

d87

55 58 60

Colon CA 54 yrs

Cervical CA 30 yrs

Cervical CA 32 yrs

34 yrs 30 yrs

CRC 79 d82

56

Case 2 TedCase 2 Ted Verify Diagnoses Obtain and review pathology reports on

all reported cancers whenever possible

If diagnoses are correct Ted has no family history indicative of a known colon cancer syndrome (HNPCC FAP other)

Tedrsquos lifetime risk of colorectal CA is increased 2 to 3 fold due to one affected first degree relative (gt50)

Moderatefamilial risk Screening by colonoscopy starting at age 40 or 10 yrs earlier than earliest case in family is reasonable

Chemo PreventionChemo Prevention Evidence that ASA NSAIDs Calcium and COX-2

inhibitors may reduce incidence of CA by reducing ofadenomas

1048707 40-50 risk reduction for developing colorectal CA regardless of location in colon age gender and race

Generally performed by RCTrsquos in patients with priorcolorectal CA followed for recurrence of adenomas

Diet fiber and antioxidant vitamins have not beenshown by RCTrsquos to decrease risk of recurrent adenomas

COX-2irsquos and Sulindac have been shown to reduce thenumber of adenomas found in FAP alone

1048707 Not effective for sporadic colon CA 1048707 Actually can cause regression of adenomas

Case 2 TedCase 2 Ted Verify Diagnoses Obtain and review pathology reports on

all reported cancers whenever possible

If diagnoses are correct Ted has no family history indicative of a known colon cancer syndrome (HNPCC FAP other)

Tedrsquos lifetime risk of colorectal CA is increased 2 to 3 fold due to one affected first degree relative (gt50)

Moderatefamilial risk Screening by colonoscopy starting at age 40 or 10 yrs earlier than earliest case in family is reasonable

Chemo PreventionChemo Prevention Evidence that ASA NSAIDs Calcium and COX-2

inhibitors may reduce incidence of CA by reducing ofadenomas

1048707 40-50 risk reduction for developing colorectal CA regardless of location in colon age gender and race

Generally performed by RCTrsquos in patients with priorcolorectal CA followed for recurrence of adenomas

Diet fiber and antioxidant vitamins have not beenshown by RCTrsquos to decrease risk of recurrent adenomas

COX-2irsquos and Sulindac have been shown to reduce thenumber of adenomas found in FAP alone

1048707 Not effective for sporadic colon CA 1048707 Actually can cause regression of adenomas

Chemo PreventionChemo Prevention Evidence that ASA NSAIDs Calcium and COX-2

inhibitors may reduce incidence of CA by reducing ofadenomas

1048707 40-50 risk reduction for developing colorectal CA regardless of location in colon age gender and race

Generally performed by RCTrsquos in patients with priorcolorectal CA followed for recurrence of adenomas

Diet fiber and antioxidant vitamins have not beenshown by RCTrsquos to decrease risk of recurrent adenomas

COX-2irsquos and Sulindac have been shown to reduce thenumber of adenomas found in FAP alone

1048707 Not effective for sporadic colon CA 1048707 Actually can cause regression of adenomas