Breast Cancer Risk Assessment and Genetic

Testing

Susan W. Caro, RNC, MSN, APNG

Director, Family Cancer Risk Service

Vanderbilt-Ingram Cancer Center

Objectives:

1. Appreciate the complex and emerging information about the impact of genetics on breast cancer risk.

2. Identify resources available for assessing genetic risk.

3. Articulate when risk counseling and assessment is recommended.

4. Know the TN resources for genetic risk assessment.

In 1990, the National Institutes of Health and the Dept. of Energy launched the Human Genome Project, an international effort to map, sequence, and characterize the human genome. Working draft completed in June 2000, published in Science and Nature in February 2001.

Why?

• Hereditary cancer syndromes are being more clearly defined with increasingly clear recommendations for management.

• Clinical genetics tests for hereditary cancer syndromes are available and in some markets are being marketed directly to the consumer.

• Recognizing hereditary cancer syndromes provides the opportunity to identify those at significantly increased risk and offer options to identify cancers earlier or prevent cancer in these individuals.

• Potential for medico-legal implications of not recognizing hereditary cancer syndromes.

Lynch HT, Paulson JD, Severen M, et al. Failure to Diagnose Hereditary Colorectal Cancer and Its Medicolegal

Implications. Dis. Colon Rectum January 1999;42:31-35.

Hereditary Cancer Burden in Tennessee?

Breast Cancer 3,720 new diagnoses 920 deaths

Colorectal Cancer 3,290 new diagnoses 1130 deaths

If ~10% hereditary cancer – 372 new cases of hereditary breast cancer (392 CRC) this year.

Could some of these have been foreseen, even prevented?

*Excludes carcinoma in situ (CIS, non-invasive cancer) of any site except urinary bladder.

Does not include basal and squamous cell skin cancers (of which there are 1.3 million per year).

American Cancer Society, 2008

Prevention (medical)

• In medicine, prevention is any activity which reduces the burden of mortality or morbidity from disease. This takes place at primary, secondary and tertiary prevention levels.

• Primary prevention avoids the development of a disease. Most population-based health promotion activities are primary preventive measures.

• Secondary prevention activities are aimed at early disease detection, thereby increasing opportunities for interventions to prevent progression of the disease and emergence of symptoms.

• Tertiary prevention reduces the negative impact of an already established disease by restoring function and reducing disease-related complications.

Wikipedia

All cancer is genetic, not all cancer is

hereditary.

Breast Cancer Genes Found

Clip

• BRCA1 (for BReast CAncer gene 1) was described in 1990 on chromosome 17, isolated in 1994

• BRCA2 was isolated on chromosome 13 in late 1994

• BRCA3?

The Development of Hereditary Cancer

1 damaged gene1 normal gene

Tumordevelops

2 normal genes 2 damaged genes

In hereditary cancer, one damaged gene is inherited.

1 damaged gene1 normal gene

Tumordevelops2 damaged genes

© 2006 Myriad Genetic Laboratories, Inc.

Myriad Genetics, Inc.

American Society of Clinical Oncology Guidelines for Genetic Testing

• Personal or family history features suggestive of hereditary cancer risk

• Test can be adequately interpreted

• Test result will aid in diagnosis or influence medical management of the patient and/or family

J Clin Oncol 2003;21:2397-406

Cancer Syndromes

• Hereditary Breast Cancer Syndromes– BRCA1, BRCA2, Cowden, CHEK2, Li-Fraumeni

• Hereditary Colorectal Cancer Syndromes– HNPCC– FAP

• Endocrine Syndromes – VHL, MEN1, MEN2, FMTC• Other – Li Fraumeni, Peutz-Jeghers• DNA Banking

Ask – out loud

• Ask the question: Do you have a family history of cancer?

• Clarify - maternal AND paternal family history• Ask the question again more specifically:

Does anyone in your family have a history of breast, ovarian, colon cancer, colon polyps, or other cancers?

• Ask the question again at follow up visits, as family histories change over time.

FCRS

Listen when your patients voice a concern:

• In many health care encounters today, we are focused on the problem at hand and it is difficult to go beyond this.

• Not suggesting that every health care provider have an expert knowledge of the complex issues surrounding all of the hereditary cancer syndromes - rather that continual exposure to this information will prompt recognition and referral for more thorough evaluation of the family.

• A significant number of our patients seek consultation independently. Their health care providers do not always recognize the significance of family history.

Refer• Refer for comprehensive risk assessment and

consideration of genetic testing.• Genetic testing is only one aspect of this. There is a

great deal to be learned from gathering and documenting the family history and the educational component of the counseling process.

• Many patients are concerned as a result of things they have read or been told about insurance discrimination. This is addressed in the counseling session (before any decision for genetic testing is made).

Family Cancer Risk Consultation

Should include:• Education about cancer risk in families• Cancer/genetic risk assessment• Discussion of possible risks and

benefits of genetic testing• Psychological support, guidance about

medical options, and referral for medical or surgical means of early detection or prevention of cancer Offit, 1998, p. 3

Comprehensive Risk Assessment / Consultation

• Assess patient’s view of their risk, experience with cancer in the family• Review what is known and not known about cancer risk• Medical history, current surveillance activity• Review family history and draw pedigree• Document cancers in history (medical record and pathology review)• Provide risk assessment - Risks associated with hereditary cancer syndromes

under consideration, risks if no recognizable syndrome• Education - Cancers, risks factors, surveillance, basic genetics, cancer

genetics• Testing? Benefits, limitations, risks, costs, insurance, process• Recommendations for surveillance or possible preventive measures, discuss

implications to others in family.• Interpretation of test results, including psychological, social, and family

implications of test results

Management Options / Counseling

• Review options for increased screening or measures to decrease risk

• Discuss efficacy (or lack of efficacy/ or lack of data to support efficacy) of surveillance, prophylactic / risk reducing, or chemopreventive measures

• Increasing understanding of utility and consequences of surveillance and intervention options – a moving target.

ASCO

How Much Breast and Ovarian Cancer Is Hereditary?

SporadicSporadic

Family clustersFamily clusters

HereditaryHereditary

Ovarian CancerOvarian CancerBreast CancerBreast Cancer

5%–10%5%–10% 5%–10%5%–10%

15%2015%20% %

Hereditary Cancer

10%

Others90%

Breast and ovarian cancers

Other16%

BRCA232%

BRCA152%

Breast Cancer Families

Other5%

BRCA214%

BRCA181%Breast and Ovarian

Cancer FamiliesKing, Rowell, Love, 1993; Ford, Easton, Stratton, et al, 1998

Contribution of BRCA1/2 to hereditary breast /ovarian cancer families:

BRCA Mutations and Ashkenazi Jews

• 185delAG mutation noted in 1% of 850 samples of Ashkenazi Jewish individuals unselected for family history of cancer (studied stored samples from Tay-Sachs research)

• Carrier rate 3 X that expected in general population

• May account for 16% of breast and 39% of ovarian cancer in AJ women <50

• 2 other “founder mutations”

Male Breast Cancer and BRCA2

Studies of BRCA2 in population- and clinic-based series of male breast cancer patients from the United States and Europe have found carrier frequencies of BRCA2 mutations of 4% - 40%The percentage of male breast cancer cases that are associated with a BRCA2 mutation varies depending on the population. Figures from various studies (some small): 4% in U.S.;

21% in Sweden; 40% in Iceland.

One study showed that among men with breast cancer and a first-degree relative (e.g., mother or sister) with breast cancer approximately 11% were carriers of a BRCA2 mutation.

For male BRCA2 alteration carriers:• Estimated cumulative risk of male breast cancer is ~6% by age 70• Age of onset not as early as female breast cancer in BRCA2 carriers•BRCA1 may account for more cases of male breast cancer than initially estimated. (Couch et al. 1996, Thorlacius et al. 1996, Friedman et al. 1997, Csokay et al. 1999)

Cumulative Risk of Breast and Ovarian Cancer in BRCA1 and BRCA2 Mutation Carriers

From Rebbeck,T; J Clin Oncol 18:100s-103s 2000

Risks of Breast Cancer with BRCA1 or BRCA2 Mutation

Breast cancer risk by age (women)

BRCA1 BRCA2 Ashkenazi women w/ BRCA1/2

General population US

40 19% 12%

50 50% 28% 33% 2%

60 64% 48%

70 85% 84% 56% 7%Easton DF, Ford D, Bishop T, and the Breast Cancer Linkage Consortium, 1995. Am J Hum Gen 56:265-271.Easton DF, et al., and the Breast Cancer Linkage Consortium, 1999. JNCI 91:1310-1319.Ford D, Easton DF, Stratton M, Narod S, et al., 1998, Am J Hum Genetics 62:676-689.Struewing JP, Harge P, Wacholder W, et al. NEJM, 1997. 336(20):1401-1408.Ford D, Easton DG, Bishop T, Narod S, 1994. Lancet 343:692-695.

Contralateral Breast Cancer Risk BRCA1/2 Mutation Carriers

BRCA1 BRCA2 BRCA1 or BRCA2

Women w/ prior hx breast cancer

Risk of new breast ca dx by age 70

60% 52% 3%/year <1% per year

The hope is that increased surveillance and/or interventions may identify cancers early or reduce the risk of cancers.

Risk assessment may also identify those not at increased risk.

Recognition: the first step in management of familial cancer risk

Cancer Clusters

• Cancer can happen in a family just by chance • Cancer can cluster in families because of shared

environmental exposures (diet, lifestyle, “environment”, work related exposures)

• Cancers may be due to inheritance of a single genetic alteration that poses very high risk of cancer

• Cancers may be due to inheritance of less penetrant genetic alterations

Sporadic/Familial/HereditarySporadic cancers

Age appropriate

Common cancers

Familial Cancer

Occurring in or affecting more members of a family than would be expected by chance” Generally, two or more family members with the same type of cancer, age appropriate

Hereditary Cancer-Multiple affected family members-Several cases of the same type of cancer or cancers known to be part of an hereditary cancer syndrome (e.g. breast & ovarian, colon & endometrial, sarcoma & breast).-Younger than expected ages of onset - such as breast < 40, colon < 50-Rare cancers in the family such as males with breast cancer-Individuals with multiple primary cancers or multifocal or bilateral cancers-Family history consistent with generation to generation transmission

Tools for risk assessment:

Breast cancer risk assessment models - Claus, Gail, BRCAPRO, Frank/Myriad models

Models for other cancers from the literature

Computer/Internet resources

Gene tests, OMIM, NCI website

Ongoing education

Models used to calculate breast cancer risks

• Claus Model - Age specific risk estimates for breast cancer, considers maternal and paternal history, age at onset, first and second degree relatives (excludes some relatives).

• Gail Model - Estimates the chance that a woman of specific age would develop breast cancer, includes age at menarche, childbirth, # of prior biopsies, and first degree relatives. Excludes paternal relatives, non-first degree relatives. Adapted to consider atypical hyperplasias.

• Tyrer-Cusick Model – (2004) Uses personal risk factors for breast cancer, and likelihood of BRCA gene mutation and a low penetrance gene to assess breast cancer risk.Claus EB, Risch N, Thompson WD, 1990;1991;1994; Gail MH, Brinton LA, Byar EP, et al, 1989; Tyrer J, Duffy SW, Cuzick J. Stat Med 2004; 23: 1111-1130

FCRS

Models used to calculate likelihood of BRCA1 or BRCA2 mutation:

• BRCAPRO - computer model, uses pedigree to calculate risk based on several different models.

• Frank or Myriad Model/Tables - use family history and personal history to estimate risk of mutation in BRCA1 or BRCA2.

• BOADICEA (Breast and Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm) – University of Cambridge computer model to assess risk of BRCA1/2 mutation.

Euhus D, Berry D, Parmigiani G, Iverson E, 1998; Frank TS, Manley SA, Olopade OI, et al, 1997, 1998. Antoniou AC, Hardy R, Walker L, Evans DG, Shenton A, Eeles R, Shanley S, Pichert G, Izatt L, Rose S, Douglas F, Eccles D, Morrison PJ, Scott J, Zimmern RL, Easton DF, Pharoah PD.J Med Genet. 2008 Jul;45(7):425-31. Epub 2008 Apr 15.

Characteristics of those families appropriate for consideration for BRCA1 or BRCA2 testing

(including patient’s personal history)

several breast cancers or breast and ovarian cancer two or more ovarian cancers in one family presence of bilateral cancers of the breast or ovary cancers diagnosed at younger than expected ages multiple affected relatives, demonstrating an autosomal

dominant pattern of inheritance presence of individuals diagnosed with more than one

cancer, e.g. breast and ovarian breast and/or ovarian cancer and Ashkenazi (Eastern

European) Jewish heritage male breast cancer

Cindy’s Story

Cindy34 yo+ BRCA2 mutation

Renee65 yoOv dx 46Br dx 52

John66 yo

Caroline2 yo

John Jr.6 yo

RickColon dx 31D. 33

James 5 yo

Katherine3 yo

Jason31 yo

Jane28 yo

BessieD.91Br Dx 91

Kate61 yo

X 3No CA

AliceD. 50? stomach

Janice61 yo

?

Susan30 yo

FCRS

Cindy’s Risk Assessment

Gail ModelRace - CaucasianAge - 34Age Menarche - 13Age 1st live birth - 28# Mother, Sister, Daughter with

Breast Cancer - 1# previous biopsy - 0

5 year risk = 0.5% lifetime risk = 19.2%

Claus ModelUsing Table of One First

Degree RelativePredicted cumulative

probability of breast cancer by age:

39 = .8%49 = 2.3%59 = 4.9%69 = 8.2%79 = 11%Benichou J, Gail M, Mulvihill J. 1996. JCO 14:103-10

Claus EB, Risch N, Thompson WD, 1994. CANCER 73:643-51.

FCRS

Hereditary Breast/Ovarian Cancer Syndrome

2

L br ca 42R br ca 55Oophorectomy (BSO) 53+ BRCA2

35

375

3

70-80No cancer

30-50No cancer

+BRCA2Bil mastectomyBil Salingo-oophorectomy365

d. 94 ht dz

Br ca 44

Ov ca 52

d. 79

d. Br ca 42

- Risk Perception - Everyone’s is Unique

• Individual’s view of “high risk”, “common”, “rare”, “unlikely” is colored by their experience and psychological make-up.

• Half-full vs. half-empty• Experience with statistics (“I will be the <1% who develops

….”)• Personal experience with cancer or cancer scares, caring

for others with cancer (especially if repeatedly or recently)• Relationships and age influence reaction - parent’s cancer

and child or adolescent vs. adult, siblings with cancer, friends with cancer.

Page DL, Caro SW, Dupont SD, 1998.

Testing Process

• Counsel/Education• Gather pedigree and documentation• Test affected individual for mutation• If family + for mutation, then can test

unaffected individuals• If + mutation in family, - mutation in individual,

individual risk is close to population risk• If no identified mutation in family, risk is

estimated based on history and empiric data

Outcome of process

• Clarify risks of cancer• Identify individuals who may not be aware of

increased risk• Identify individuals who may not be at

increased risk• Identify those appropriate for increased

cancer surveillance, or measures to decrease risk (prophylactic surgery, chemoprevention), or those appropriate for research on surveillance or chemoprevention

Options for Women at Risk

Increased Surveillance

Risk-reducing Surgery

Medical Intervention

FCRS

Increased Surveillance

Breast Cancer• Clinical examination every

6 months• Mammogram yearly

beginning age 25-35• MRI (ACS 2007)• Monthly BSE• Prompt evaluation of

abnormal findings

Ovarian Cancer

• Ca-125• Pelvic color-doppler

ultrasound every 6-12 months

• Pelvic examination every 6-12 months

ACS Recommendations for Breast MRI Screening as an Adjunct to Mammography 2007

Recommend Annual MRI Screening (Based on Evidence*)  BRCA mutation   First-degree relative of BRCA carrier, but untested   Lifetime risk 20–25% or greater, as defined by BRCAPRO or other models that are largely dependent on family

historyRecommend Annual MRI Screening (Based on Expert Consensus Opinion )   Radiation to chest between age 10 and 30 years   Li-Fraumeni syndrome and first-degree relatives   Cowden and Bannayan-Riley-Ruvalcaba syndromes and first-degree relativesInsufficient Evidence to Recommend for or Against MRI Screening    Lifetime risk 15–20%, as defined by BRCAPRO or other models that are largely dependent on family history   Lobular carcinoma in situ (LCIS) or atypical lobular hyperplasia (ALH)   Atypical ductal hyperplasia (ADH)  Heterogeneously or extremely dense breast on mammography   Women with a personal history of breast cancer, including ductal carcinoma in situ (DCIS)Recommend Against MRI Screening (Based on Expert Consensus Opinion)   Women at <15% lifetime risk* Evidence from nonrandomized screening trials and observational studies. Based on evidence of lifetime risk for breast cancer. Payment should not be a barrier. Screening decisions should be made on a case-by-case basis, as there may be particular factors to support MRI. More

data on these groups is expected to be published soon.

CA Cancer J Clin 2007; 57:75-89

Risk-Reducing Surgery

Mastectomy

Total mastectomy vs.. subcutaneous mastectomy?

Not 100% effective, true risk reduction unclear, >90%.

Hugely personal decisions.

OophorectomyUnfortunately not 100% effective in

eliminating ovarian cancer risk, as intraabdominal carcinomatosis has occurred (2-4%)

Questions - hysterectomy?HRT?, do we screen after BSO

Bilateral oophorectomy reduced risk of breast cancer in BRCA1 mutation carriers. (RR=0.53). HRT did not

negate reduction in risk.Rebbeck TR, Levin AM, Eisen A, et al. JNCI 91(17):1475, Stuewing JP, Watson P, Easton DF, et al JNCI Monographs 1995. 17:330; Eisen A, Rebbeck TR, Wood WC,Weber BL. JCO 18(9)”1980; May 2000. Hartmann LC, Daniel JS, Woods JE, et al. NEJM 340(2):77-84, Jan 14, 1999;

Medical InterventionsBreast Cancer

• Risk reducing medications should be discussed based on current understanding.

Ovarian Cancer• Oral contraceptives have been

shown to decrease the risk of ovarian cancer in the general population.

• In women with mutations in BRCA1 or BRCA2 that risk reduction was also documented, with 60% reduction (RR=0.4) with use of 6 years or more.

Narod SA, Risch H, Moslehi R, et al. NEJM 1998, Aug 13;339(7):469-71.Fisher B, Costantino JP, Wickerman DL, et al. JNCI, 1998; 90(18):1371-1388.

Misconceptions about genetic testing:

1. Testing is not covered by insurance. In most instances insurance covers the cost of testing like any other medical expense.

2. Testing is complicated. True and false – choosing the appropriate test is not always simple, there are significant opportunities for misinterpretation. Seek consultation with a health care provider (nurse practitioner, genetic counselor, MD) specializing in hereditary cancer.

3. Testing will cause you to lose your insurance. Concerns exist about genetic discrimination, but after nearly 15 years of clinical testing, no significant problems have been seen. Members of group health insurance plans have protection under Federal Law (HIPPA, 1996). GINA signed into law May 2008, extends protections from discrimination based on genetic information to those with private health insurance

“Walking with the Ghosts of

My Grandmothers”

a painting by Hollis Sigler

on the cover ofthe journal Science

October, 1994

Hereditary Diffuse Gastric Cancer Syndrome

Autosomal dominant inheritanceGermline mutations in CDH1/E-Cadherin Gene

(described in hereditary gastric families in 1998)Initially found in Maori families, since described in

families from many ethnic groups.Penetrance thought to be 70%, Also increased risk of colon cancer and breast

cancer

•An autosomal dominantly inherited hamartoma syndrome with an incidence of at least 1/200,000 (probably an underestimate)

(hamartomas are benign, disorganized growths)

•characterized by multiple hamartomas that can occur in any organ of the body•pathognomonic cutaneous feature is the trichilemmoma, a benign tumor derived from outer-root sheath epithelium of a hair follicle

•Carries a high risk of breast, thyroid, and endometrial cancers

•Variable expression

•Highly penetrant: •Usually presents by the late teens to the late 20’s•90% of individuals with CS have symptoms by age 20•By the 3rd decade, 99% of affected individuals would have developed mucocutaneous lesions•Age-dependent penetrance: only 10% exhibit symptoms by age 10

Cowden syndrome

•Associated with inherited alterations in the gene, PTEN (‘phosphatase and tensin homolog deleted on chromosome ten’), also sometimes called MMAC1 (‘mutated in multiple advanced cancer’) which was isolated in 1997

•PTEN is located on chromosome 10q23

•Function of PTEN: •Tumor suppressor•Controls pathway for regulation of cell proliferation and cell survival

•Alterations in PTEN also associated with Bannayan-Riley-Ruvalcaba (BRR) syndrome and a small percentage of cases of juvenile polyposis syndrome (JPS).

Cowden syndrome

Cowden Syndrome

Cancer Risks Associated with Cowden Syndrome:Female Breast Cancer 25%-50% lifetime risk (vs ~11% in general pop.) Average age of diagnosis may be around age 38-46

Thyroid Carcinoma 3%-10% lifetime risk (vs 1% in general population) Non-medullary Usually follicular, but can be papillary

Endometrial Cancer 5-10%Other cancers may be associated with Cowden syndrome:

Genitourinary Mucocutaneous Male BreastGastrointestinal

Central Nervous System medulloblastomas are more common

Other, e.g. liposarcoma

Li-Fraumeni Syndrome

• Initially described by Frederick Li and Joseph Fraumeni (1969) as syndrome associated with sarcomas and other diverse tumors.

• Associated cancer include soft-tissue sarcoma, osteosarcoma, early-onset breast cancer, brain tumors, adrenocortical carcinoma, and leukemias, primarily acute leukemia. (Was also called SBLA for Sarcoma, Breast/Brain, Leukemia, and Adrenal)

• Inherited in an autosomal dominant manner.• Other reports have associated other cancers - including

melanoma, cancers of the stomach, pancreas, colon, and esophagus, and gonadal germ cell tumors.

• Gene mutations TP53 (1990) on 17p13, possibly others

DNA BANKING

If genetic testing is not possible or not informative, DNA banking is a relatively inexpensive and simple procedure that can save a sample of the affected person’s DNA for future testing.

Resources to find cancer genetics professionals in your area:

• http://www.cancer.gov/search/genetics_services/

• genetests.org

• http://www.nsgc.org/resourcelink.cfm

Disparities….

Family Cancer Risk Service of the Vanderbilt-Ingram Cancer Center is

made possible by support from:

From Generation to Generation © 1998 Jay M. Rotberg, artist and sculptor

Vanderbilt-Ingram Cancer CenterTennessee Breast Cancer CoalitionSusan G. Komen Foundation, Greater Nashville Affiliate (past)Our physician consultants:Mark Kelley, Ingrid Meszoely,Marta Crispens, John Phay, Paul Wise

And the individuals and families who seek counsel

Family Cancer Risk Service of the Vanderbilt-Ingram Cancer

Center

From Generation to Generation © 1998

Jay M. Rotberg, artist and sculptor

Susan Caro, RNC, MSN, APNGDirector

Kate McReynolds, MSc, RN

Telephone: (615) 343-0738or TOLL FREE: 1-877-688-7555

Selected Hereditary Cancer Syndromes

Hereditary Breast/ovarian cancer BRCA1, BRCA2, CHEK2 Other?

Breast, ovarian prostate, pancreatic r (BRCA2), ? Colon and other cancers

Site specific breast cancer BRCA1, BRCA2 Breast

Site specific ovarian cancer BRCA1, BRCA2 Ovarian

Li-Fraumeni Syndrome TP53, CHEK2 Breast, sarcomas, adrenocortical carcinoma, leukemia, brain tumors

Cowden PTEN Breast, thyroid, benign lesions of skin, breast, thyroid; renal cell carcinoma

Peutz-Jegher Syndrome STK11 Breast cancer, benign ovarian tumors, testicular tumors, pancreatic cancer, polyps (ureter, bladder, GI tract, renal pelvis, characteristic skin lesions (melanin spots, lips, buccal mucosa

Familial adenomatous polyposis APC, MYH Polyposis, colorectal cancer, thyroid gastric cancer, periampullary carcinoma, hepatoblastoma

Variant of FAP - Attenuated FAP APC <100 colorectal polyps, later age onset CRC, gastric, duodenal adenomas or cancer

Variant of FAP - Gardner’s Syndrome APC Osteomas of skull and mandible, CHRPE, dental anomalies, lymphangiomas, lipomas, desmoids

HNPCC (Lynch Syndrome) MLH1, MSH2, MSH6

, PMS1, PMS2,

Colorectal cancer (often right sided and multifocal), endometrial ca, ovarian ca, small bowel, stomach, pancreas, ureter, renal pelvis

Turcot’s Syndrome APC, MMR genes Colorectal adenomas, CRC, primary brain tumors (mudulloblastoma APC, glioblastoma MMR)

OMIM, Elsas LJ, Trepanier A. Cancer Genetics in Primary Care. Postgraduate Medicine 107(4):191-208, April 2000., Offit K. Clinical Cancer Genetics, Wiley-Liss, 1998, New York.

Selected Hereditary Cancer Syndromes (cont’d)

MEN MEN1, RET Multiple endocrine cancers

Retinoblastoma RB1 Retinoblastoma, often bilateral and < 1 year of age, also associated increased risk of sarcoma, melanoma, brain tumors

Von Hippel-Lindau VHL Renal cell carcinoma, retinal angioma, cerebellar hemangioblastoma, pheochromocytoma, pancreatic cysts, islet cell tumor

Prostate cancer HPC1, BRCA1, p53 Earlier age onset prostate cancer, maybe part of other syndromes

Pancreatic cancer BRCA2, MADH4, TP53, CDKN2A, ARMET, +++

Other syndromes, HNPCC, HBOC, Li-Fraumeni, VHL, melanoma, hereditary pancreatitis, site specific pancreatic ca

Melanoma P16, CDK4, others Melanoma, dysplastic nevi, pancreatic ca

OMIM, Elsas LJ, Trepanier A. Cancer Genetics in Primary Care. Postgraduate Medicine 107(4):191-208, April 2000., Offit K. Clinical Cancer Genetics, Wiley-Liss, 1998, New York

Stigmata of Selected Syndromes Associated with Susceptibility to Cancer

Cowden Syndrome Breast cancer Facial papules, oral “cobblestone” papules, macrocephaly

Down Syndrome Acute leukemia Characteristic facies, round head, congenital heart disease

Fancomi Anemia Acute leukemia Upper extremity malformations, increased skin pigmentation

FAP (Gardner’s subtype) Colon cancer Retinal pigmentation, sebaceous cysts, osteomas, impacted teeth, exostoses, , desmoids, florid polyposis

Muir-Torre syndrome Colon cancer, skin tumors Sebaceous adenomata, keratocanthomata, basal cell carinomas,

Multiple Endocrine Neoplasia type 2b

Medullary thyroid carcinoma, pheochromocytoma,

Enlarged and nodular lips, Marfanoid habitus

Peutz-Jegher syndrome Breast, colon cancers Dark spots on lips, perioral areas, buccal mucosa and extremeties

Turcot syndrome Colon cancer, brain tumors Polyps, café-au-lait spots, sebaceous cysts on skin

“WAGR” syndrome (Wilm’s tumor, aniridia, genitourinary abnormalities and mental retardation)

Wilm’s tumor Aniridia, genitourinary malformations

Syndrome Major Cancer Risks Selected physical findings

Offit, K. Clinical Cancer Genetics, Risk Counseling & Management, Wiley-Liss, New York, 1998.

RED FLAGS – Think about hereditary susceptibility when you see:

• Breast Cancer at age less than 50• Ashkenazi Jewish heritage and breast or ovarian• More than one ovarian cancer in a family, or breast and

ovarian cancer• Men with breast cancer• More than one pancreatic cancer in a family• Colorectal cancer less than 50 years of age• Polyposis• Pheochromocytoma• Medullary thyroid cancer