COLON CANCER & GENETICS VERMONT COLORECTAL CANCER SUMMIT NOVEMBER 15, 2014

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1 COLON CANCER & GENETICS VERMONT COLORECTAL CANCER SUMMIT NOVEMBER 15, 2014 WENDY MCKINNON, MS, CGC CERTIFIED GENETIC COUNSELOR FAMILIAL CANCER PROGRAM UNIVERSIT Y OF VERMONT MEDICAL CENTER 1

2 CHARACTERISTICS OF HEREDITARY COLORECTAL CANCER Multiple relatives with colorectal cancer on same side of the family (maternal or paternal lineage) Early age at diagnosis of colon cancer (<50) Multiple primary tumors in same individual Multiple colon polyps Other benign and/or malignant tumors in the family known to be associated with inherited CRC INHERITED CRC: ADENOMATOUS Lynch syndrome / HNPCC Autosomal dominant Variants: Turcot, Muir-Torre Genes: MLH1, MSH2 (EPCAM), MSH6, PMS2 Familial adenomatous polyposis (FAP) Autosomal dominant Variants: AFAP, Gardner, Turcot Gene: APC Multiple adenomatous polyposis (MAP) Autosomal recessive Gene: MUTYH 2

3 INHERITED CRC: HAMARTOMATOUS Peutz-Jegher syndrome (PJS) Gene: STK11 Juvenile Polyposis (JP) Genes: SMAD4, BMPR1A Mutations in SMAD4 also associated with HHT Cowden syndrome (CS) Variant: Bannayan-Ruvalcaba-Riley (BRR) Gene: PTEN * All are autosomal dominant LYNCH SYNDROME Accounts for at least 3% all colon cancers Characteristics: Early age onset Proximal tumors Pathologic characteristics Extra-colonic cancers LS accounts for at least 3% all endometrial cancers Gastric, small intestine, urinary tract, ovarian, hepatobiliary, sebaceous skin tumors, and glioblastomas 3

4 LIFETIME CANCER RISKS FOR LS Cancer site MLH1 MSH2 MSH6 PMS2 Any Lynch cancer 44-79% 38-78% 25-65% 16-53% Colorectal Men Women 58-65% 50-53% 53% 54-63% 39-68% 36-69% 69% 18-30% 20% 15% Endometrial 57-66% 21% 17-44% 15% Lynch syndrome Surveillance Options Intervention Colonoscopy Endometrial sampling Transvaginal US Upper endoscopy Recommendation Every 1-2 y beginning at age (MLH1 & MSH2), or age 30 (MSH6 & PMS2). Annual after age 40. Annual beginning at age Consideration of TAH/BSO Periodic Urinalysis Every 1-2 y beginning at age History & Exam w/ review of systems Annual beginning at age 21 Lindor et al, 2006; Vasen et al, 2007; Lu

5 APPROACHES TO DIAGNOSING LYNCH SYNDROME Family history / clinical criteria Tumor based testing Molecular / DNA based testing Multi-gene panels Tumor genomics THE FAMILY HISTORY AND DIAGNOSING LYNCH SYNDROME CRC dx 50s CRC dx 45 CRC dx 61 CRC dx 75 Ovarian Ca, dx 64 CRC dx 48 CRC dx 52 Endometrial Ca, dx CRC dx 42 5

6 CLINICAL CRITERIA Many families do not meet current clinical criteria for Lynch syndrome Amsterdam Criteria I and II Bethesda Criteria, original and revised Hampel, et al NEJM, 2005 Screened 1500 CRC; 44 LS mutation carriers 50% CRC diagnosed after age 50 25% did not meet AC or BC GENETIC FEATURES OF LYNCH Genes belong to DNA mismatch repair (MMR) family Mutations in MMR genes lead to microsatellite instability (repetitive sequences of DNA) MMR proteins are missing in the tumor tissue 6

7 IMMUNOHISTOCHEMISTRY Identify MMR proteins normally present If protein is absent, gene is not being expressed (mutation or methylation) Helps direct gene testing by predicting likely involved gene MLH1 MSH2 PMS2 MSH6 ABNORMAL MLH1 & PMS2 ABSENT 15% of the time 80% acquired methylation of MLH1 MLH1 MSH2 20% will be LS MSH6 PMS2 7

8 ABNORMAL MSH2 & MSH6 ABSENT 3% of the time Most likely LS due to either MSH2 or MSH6 gene mutation MLH1 MSH2 Refer to Genetics for GC and GT MSH6 PMS2 ABNORMAL MSH6 OR PMS2 ABSENT 2% of the time Most likely LS due to an MSH6 or PMS2 gene mutation MLH1 MSH2 Refer to Genetics for GC and GT MSH6 PMS2 8

9 EVIDENCE FOR UNIVERSAL SCREENING Columbus-area HNPCC studies NEJM 2005;352: ; J Clin Oncol 2008;26: EGAPP Recommendations All CRC be screened for LS; Genet Med, 2009,11:35-41 Cost-effectiveness evaluations Genet Med, 2010, 12:93-104; Ann Int Med, 2011, 155:69-79 Healthy People 2020; Institutions adopting universal screening 71% NCI Cancer Centers 28% COC Accredited Cancer Centers 15% Community Cancer Centers POTENTIAL IMPACT 146,970 new cases of CRC in the US 4,115 have Lynch syndrome (2.8%) 12,345 of their relatives have LS (~3 per proband) Total of 16,460 individuals who could be diagnosed with LS by universal screening on colon cancers 9

10 IMPLICATIONS OF DIAGNOSIS OF LYNCH SYNDROME For cancer patient with LS diagnosis: Increased risk of second primary cancer 50% after 20 years Guidelines differ for cancer patients with/without LS For relatives: Individualize screening for relatives with/without LS Early diagnosis / prevention UNIVERSAL SCREENING FOR LYNCH SYNDROME AT FAHC/UVMC , a targeted approach was used Jan 2012, all colon cancers tested for Lynch syndrome colon resections biopsies under age 50 September 2014, switched to testing all biopsies containing cancer regardless of age IHC is screening tool used 10

IHC LETTER COMMUNICATION OF RESULTS Genetic Counselor notified by pathology of all results For abnormal results, GC asks permission of ordering physician to

11 IHC LETTER COMMUNICATION OF RESULTS Genetic Counselor notified by pathology of all results For abnormal results, GC asks permission of ordering physician to contact patient Patient contacted and GC appointment scheduled All results entered into database housed in the EMR All patients with normal results sent letter 11

12 PRISM (EPIC) Document Flowsheet NORMAL IHC RESULT LETTER 12

13 GENES ASSOCIATED WITH INCREASED COLON CANCER RISK Established Guidelines MLH1 MSH2 MSH6 EPCAM PMS2 APC MUTYH SMAD4 BMPR1A TP53 STK11 Newer genes; no established guidelines CHEK2 GREM1 GALNT12 POLE POLD1 13

14 FAMILY HISTORY Family history is key component Thanksgiving is National Family History Day Access the My Family Health Portrait Web tool at THANK YOU! Contact Information: Familial Cancer Program (802)

Genetic testing all you need to know

Genetic testing all you need to know Sue Clark Consultant Colorectal Surgeon, St Mark s Hospital, London, UK. Colorectal cancer Familial 33% Polyposis syndromes