Genetic Testing and Management of the Hereditary...

Carol A. Burke, MD, FACG

Genetic Testing and Management of the Hereditary Gastrointestinal

Cancer SyndromesCarol A. Burke, MD, FACG

Sanford R. Weiss MD Center for Hereditary Colorectal NeoplasiaDepartment of Gastroenterology and Hepatology

Cleveland Clinic, Ohio

Objectives

• Identify phenotype of hereditary CRC syndromes• Utilize tumor testing in Lynch Syndrome (LS)• Recognize criteria for germline genetic testing

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ACG 2016 Southern Regional Postgraduate Course Copyright 2016 American College of Gastroenterology

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Pathways to CRC

Adenoma Serrated Neoplasm

FAP MYH

Lynch Syndrome

Sporadic CRC

CIN-MSS CIMP-MSS/MSI

MSI

MLH1 promotor methylationBRAF mutation

MSI

Lynch Syndrome• Present in 1:350 individuals, causes 5% of CRC• Caused by germline mutation in a MMR gene

– MLH1, MSH2, EPCAM MSH6, PMS2• Causes tumor signature called microsatellite instability, MSI• MSI detected through pathology lab

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MLH1 MSH2

ImmunohistochemistryBAT25

Tumor Tissue

Normal Tissue

MSI


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Hereditary Colon Cancer SyndromesSyndrome Features

Lynch Syndrome Colorectal, endometrial, ovarian, gastric, urothelial, small bowel, skin and brain Ca

Li Fraumeni Syndrome Childhood cancers, sarcoma, leukemia, brain tumors, breast cancer, CRC

Familial Adenomatous Polyposis Adenomas, CRC, duodenal, gastric, thyroid cancer, osteomas, sebaceous cysts, CHRPE, adrenal and desmoid tumors

MYH-Associated Polyposis Adenomas, CRC, duodenal cancer, thyroid cancer

NTHL1- associated Polyposis Adenomas, CRC, endometrial cancer

Polymerase proofreading associated polyposis Adenomas, endometrial cancer, brain cancer

Peutz-Jeghers Syndrome Mucocutaneous melanin, hamartomas, breast, CRC, SB, GI, lung, pancreatic, and gonadal tumor/cancers

PTEN Tumor Hamartoma Syndrome Hamartomas, dermatologic lesions, macrocephaly, breast, thyroid, endometrial, renal, colorectal cancers

Juvenile Polyposis Syndrome Hamartomas, colon, gastric cancer, HHT in patients with SMAD4 mutations5

Recognizing Hereditary CRC Personal History• Age of onset of intestinal and

extra-intestinal tumors• Pathology of tumors• Number of polyps• Head circumference (CS)• Extra-intestinal features

(epistaxis or GIB : JPS-SMAD4)

Family History • Gather in 3 generations• Occurrence and age of

cancer diagnosis• Age and cause of death• Presence of features within

spectrum of HCRC

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Risk Assessment Tool

1. Do you have FDR with any of the following < age 50?1. CRC2. Uterus, ovary, stomach, small intestine, urinary tract, bile ducts,

pancreas or brain cancer

2. Have you had any of the following diagnosed < age 50?1. CRC2. Colorectal polyps

3. Do you have 3 or more relatives with CRC?Kastrinos et al. Am J Gastro 2009;104:

Risk Assessment Tool

1. Do you have FDR with any of the following < age 50?1. CRC2. Uterus, ovary, stomach, small intestine, urinary tract, bile ducts,

pancreas or brain cancer

2. Have you had any of the following diagnosed < age 50?1. CRC2. Colorectal polyps

3. Do you have 3 or more relatives with CRC?Kastrinos et al. Am J Gastro 2009;104:

Yes identifies up to 95% of LS patients


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Amsterdam Criteria I for HNPCC

= unaffected

= affected CRC

• >3 relatives with CRC• >2 successive generations• 1 FDR to other 2• 1 CRC diagnosed <50 yrs• FAP excluded

Vasen HF et al, Dis Colon Rectum 1991

Your patient age 38

Dx 72

Dx 63

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Amsterdam Criteria I for HNPCC

= unaffected

= affected CRC

• >3 relatives with CRC• >2 successive generations• 1 FDR to other 2• 1 CRC diagnosed <50 yrs• FAP excluded

Vasen HF et al, Dis Colon Rectum 1991

Your patient age 38

Only 50% of patients who meet AC I have LS

Dx 72

Dx 63

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Other Criteria for HNPCC

Amsterdam Criteria II • >3 relatives with HNPCC-

associated Ca (CRC, SB endometrial, urothelial)

• ≥2 successive generations• 1 FDR to other two• 1 Ca dx <50 yrs• FAP excluded

Revised Bethesda Criteria• CRC diagnosed <50 years• Synchronous or metachronous

CRC or LS-associated tumor • CRC with MSI-high pathology

features diagnosed <60 years• Patient with CRC and >1 FDR with

LS-associated tumor diagnosed <50 years or 2 FDR or SDR at any age

11Vasen H, Gastroenterology 1999;116:1453–8 Umar A. et al. J Natl Cancer Inst. 2004;18;96(4):261-8

Accuracy of Methods to Diagnose LSCriteria Sensitivity Specificity

Clinical CriteriaAC II 0.22 0.98Revised Bethesda Guidelines 0.82 0.77

Prediction ModelsMMRpredict 0.69 0.90MMRPro 0.89 0.85PREMM1,2,6 0.90 0.67

Tumor TestingMSI 0.85 0.90IHC 0.83 0.89

12Giardiello FM, MSTF; Am J Gastro 2014


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Importance of Universal Testing for LS• 1066 unselected CRCs

– 19.5% MSI; 21 patients diagnosed with LS– 43% diagnosed >50 yrs– 22% didn’t meet AC II or Bethesda guidelines

Hampel H et al. NEJM 2005;352;18

Germline Testing Results In 21 Relatives

Relationship Tested Positive Negative

First degree 54 25 29

Second degree 22 10 12

> Third degree 41 17 24

Total 117 52 65

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Test all CRCs for MSI: “Universal Testing”

• Evaluation of Genomic Applications in Practice and Prevention

• US Multi-Society Task Force on Colorectal Cancer

• American College of Gastroenterology

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Genet Med 2009:11(1):35–41

Giardiello FM , Am J Gastro 2014;109:1159

Syngal S, Am J Gastroenterol 2015; 110:223–262


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Cancer Risk in AC I FamiliesImpact of MSI vs MSS

* P<.001 Compared to SEER Lindor N, JAMA. 2005;293:1979-1985

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Site of Cancer SIR

161 families MSI(N=1855)

CRC 6.1*

Uterus 4.1*

Stomach 4.6*

Kidney 2.6*

Ovary 2.0*

Small Intestine 7.6*

Ureter 9.0*

Site of Cancer SIR

No MSI(N=1567)

CRC 2.3*

Uterus 0.8

Stomach 1.4

Kidney 0.9

Ovary 1.5

Small Intestine 1.6

Ureter 2.9

Site of Cancer SIR

MSI(N=1855)

No MSI(N=1567)

P value

CRC 6.1* 2.3* <0.001

Uterus 4.1* 0.8 <0.001

Stomach 4.6* 1.4 0.008

Kidney 2.6* 0.9 0.04

Ovary 2.0* 1.5 0.60

Small Intestine 7.6* 1.6 0.10

Ureter 9.0* 2.9 0.29

Cancer Risk in AC I FamiliesImpact of MSI vs MSS

* P<.001 Compared to SEER Lindor N, JAMA. 2005;293:1979-1985

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Site of Cancer SIR

161 families MSI(N=1855)

CRC 6.1*

Uterus 4.1*

Stomach 4.6*

Kidney 2.6*

Ovary 2.0*

Small Intestine 7.6*

Ureter 9.0*

Site of Cancer SIR

No MSI(N=1567)

CRC 2.3*

Uterus 0.8

Stomach 1.4

Kidney 0.9

Ovary 1.5

Small Intestine 1.6

Ureter 2.9

Site of Cancer SIR

MSI(N=1855)

No MSI(N=1567)

P value

CRC 6.1* 2.3* <0.001

Uterus 4.1* 0.8 <0.001

Stomach 4.6* 1.4 0.008

Kidney 2.6* 0.9 0.04

Ovary 2.0* 1.5 0.60

Small Intestine 7.6* 1.6 0.10

Ureter 9.0* 2.9 0.29

Familial CRC Type X


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Yield of Biopsy of Adenomas in LS

• Maximize preoperative diagnosis of LS• Biopsy all CRCs• Consider biopsy of adenomas for IHC if:

• Proximal, large, in patient <40 years old• Patient with adenoma and family history HNPCC or LS

Detection of MMR in Adenomas in Lynch Syndrome

Adenoma Size MSI-H IHC<5 mm (N=22) 32% 38%5-9 mm (N=7) 29% 57%>10 mm (N=6) 100% 100%

Yurgelun MB, Cancer Prev Res 2012:5;574

Extended Colectomy Decreases CRC recurrence in LS

• Comparison: Extended vs segmental colectomy• Recurrence: 0% in extended colectomy cohort

CRC Risk In Segmental Colectomy Cohort

Parry S, et al Gut 2011;60:950-95718


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MSI/IHC

Loss MLH1

BRAF mutation (+) and/or MLH1promoter methylation (+)

Sporadic Cancer

BRAF mutation (–) and/or MLH1 promoter methylation (-)

Genetic assessment and germline testing for MLH1 mutation

Loss MSH2, MSH6, PMS2

Germline testing directed by IHC

Tumor Testing based Patient Care

Giardiello, MSTF, Am J Gastro 2014:109

Manage patient and family according to genetic test results

19Follow sporadic CRC Guidelines

Tumor Testing based Patient CareCRC

MSI/Abnormal IHC

Germline MMR

Mutation

Lynch Syndrome

No MSI

Familial Colorectal

Cancer Type X

20Follow LS guidelines

Colonoscopy every 3-5 years

Sporadic


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Tumor Testing based Patient CareCRC

MSI/Abnormal IHC

No Germline Mutation Detected

Lynch Like Syndrome

*Bi-allelic Somatic MMR

mutations

Germline MMR

Mutation

Lynch Syndrome

No MSI

Familial Colorectal Type X

or Sporadic

*Mensenkamp, Gastro 2014;146:643

21Follow LS guidelines

Follow Sporadic CRC guidelines

Cancer Surveillance in LSOrgan Age to Begin Method Interval

Colon 20-25 yrs* Colonoscopy 1-2 yrs

Uterus/Ovary 30-35 yrs TVUS, Endometrial Bx 1-2 yrs

After childbearing or age 40

TAH-BSO

Stomach/SB 30-35 yrs EGD-bx H pylori 2-3 yrs

Urothelium 30-35 yrs Urinalysis 1 yr

*Or 10 years younger than the youngest age of the affected relative (2-5 yrs if relative <25 yrs)

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Giardiello F, Gastro 2014;147:502Syngal S, Am J Gastroenterol 2015; 110:222


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Adenomatous Polyposis SyndromesFAP• Due to APC mutation• Autosomal dominant• Affects 1:10,000 individuals

– 30% cases de novo• 60-100% risk of CRC

MAP• Due to bi allelic MYH mutations• Autosomal recessive • Usually <100 adenomas

– (lymphoid aggregates)

• 2-3% population carriers• 60% risk of CRC

Colorectal Phenotype and Genotype

Grover S, et al. JAMA. 2012;308(5):485-492


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Prevalence of extra-intestinal features of FAP/MAP

Desmoid tumors (15%) Thyroid carcinoma (2-17%) Adrenal adenoma (7-13% ) Osteomas (50-90%) Supernumerary teeth (11-27%) CHRPE (70-80%) Soft tissue tumors (50%)

Lipoma, fibroma, sebaceous cysts Hepatoblastoma (<2%)

Gastric features of FAP/MAP• Fundic gland polyposis

– Prevalence: 88%– Histology

• LGD: 38%• HGD: 3%:

• Gastric adenomas– Prevalence: 10%– Usually antrum

• Gastric Cancer: IncreasingCHRPE

Bianchi L, Burke CA, et al. Clin Gastro Hep 2007;6:180


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Duodenal features of FAP• Duodenal adenomas

– Prevalence: 100%• Adenomatous papilla1

– 54% if papilla appears normal – 89% if papilla appears abnormal– TIP: EGD with papilla bx to help establish diagnosis

• Periampullary/Duodenal cancer– Risk based upon duodenal polyposis stage

2Groves C Gut 2002;50:6361Burke C, GIE 1999;49:358

Staging of Duodenal Polyposis1 point 2 points 3 points

No. of polyps 1-4 5-20 >20

Polyp size (mm) 1-4 5-10 >10

Histology Tubular TVA Villous

Dysplasia Mild Moderate Severe

Spigelman AD. Lancet 1989;2: 783

Stage Points Cancer Risk1 EGD Interval*

0 0 0% 4 yrs

I 1-4 0% 2-3 y

II 5-6 2.3% 1-3 y

III 7-8 2.4% 6 -12 m

IV 9-12 36% Duodenectomy vs

3 - 6 m

Groves C Gut 2002;50:636*Syngal S, Am J Gastroenterol 2015; 110:223; 1Groves C Gut 2002;50:636


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Surveillance of FAP/MAPPhenotype Procedure Age (yrs) Interval (yrs)

Classic FAP FS or colonoscopy 10-15 1

aFAP/MAP Colonoscopy 18-20/

25-30

1-2

Surgical Consult When polyps detected

Post operative FS or pouchoscopy NA 1

Thyroid Thyroid Ultrasound Late teens 1

Duodenum EGD- duodenoscopy 20-25 Based on stage

NCCN guidelines Genetic/Familial High Risk Assessment Colorectal. version 1.2015

Genetic Testing IndicationsLynch Syndrome testing• AC I or II• Revised Bethesda Criteria• Family History of LS• Endometrial Cancer <50• >5% risk of LS based on

predictive models

APC and MYH* testing• Personal history of >20 adenomas or

>10 adenomas with other features• Family hx of APC or MYH mutation• Desmoid, hepatoblastoma, papillary

thyroid cancer, CHRPE (multi focal, bilateral)

• *Serrated Polyposis Syndrome (criteria 1 and 3 with some adenomas)


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Serrated Polyposis Syndrome WHO Criteria

1. >5 SP above sigmoid, >2 are >10 mm 2. >1 SP above sigmoid and FDR with SPS3. >20 SP distributed throughout the colon

1Snover, et al. WHO Classification of tumours of the digestive system. Berlin: Springer-Verlag; 2010

Conclusions

• HCRC phenotype includes CRC and extra-colonic manifestations

• Utilize tumor testing in Lynch Syndrome (LS)• Germline genetic testing used for diagnosis of

hereditary polyposis syndromes

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