Risk of Colorectal Cancer (CRC) Hereditary Syndromes in GI Cancer GENETIC MALPRACTICE

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1 Identifying the Patient at Risk for an Inherited Syndrome Sapna Syngal, MD, MPH, FACG Director, Gastroenterology Director, Familial GI Program Dana-Farber/Brigham and Women s Cancer Center Associate Professor of Medicine Harvard Medical School Risk of Colorectal Cancer () General population Personal history of colorectal neoplasia Hamartomatous polyposis syndromes HNPCC mutation 5% 15% 20% 15% 40% 70% 80% 60% - >95% Lifetime risk (%) Hereditary Syndromes in GI Cancer Hereditary Colorectal Cancer Familial Adenomatous Polyposis Hereditary Nonpolyposis Colorectal Cancer Hamartomatous Polyposis Syndromes Hereditary Pancreatic Cancer Hereditary Gastric Cancer GI cancers associated with other hereditary syndromes How is management of hereditary cancers different than sporadic cancers? Screening and surveillance post treatment of primary cancer Surgical management of cancer Surveillance for associated cancers Screening and surveillance of family members Reproductive counseling Causes of Hereditary Susceptibility to GENETIC MALPRACTICE Sporadic (65% 85%) Familial (10% 20%) Rare syndromes Hereditary (<0.1%) nonpolyposis colorectal JP, PJS,?LFS Familial adenomatous cancer (HNPCC) (5%) polyposis ( and MAP) (1%) Adapted from Burt RW et al. Prevention and Early Detection of,, 1996 Failure to make diagnosis and use proper diagnostic tools (family history and genetic tests) Failure to recommend adequately aggressive cancer surveillance Failure to recommend surveillance for associated cancers Failure of duty to warn family members 1

2 Case A: A 45 year old presents with rectal bleeding. Colonoscopy reveals numerous (approximately 40-50) polyps, most are <1 cm in size, a few are cm. 1. What is the differential diagnosis? 2. What is the approach to his surgical management? 3. What are the other tests that you would recommend? 4. What genetic tests would you order? 5. What are the recommendations for his children? Variations of classic phenotypes are common de novo mutation, 45 De novo germline mutations occur in ~30% of cases MAP may explain this type of pedigree Attenuated forms of polyposis occur suspect if >10 adenomas Clinical Features of Classic Family With APC Mutation Estimated penetrance for adenomas and cancer >90% Risk of extracolonic tumors (upper GI, desmoid, osteoma, thyroid, brain, other) Recognition of phenotype is easy in an affected individual Majority of classic cases due to germline APC mutations Age 40 APC d , d. 31 Age 59 Age 52, 22 colectomy Age 42 38, APC+ Age 16 Age 14 APC+ APC Negative sigmoidoscopies (age 33) Mutation carrier and MYH : A new paradigm in inherited colon cancer risk Autosomal dominant (, HNPCC) X X X + Al-Tassan, Nat Genet, 2002 Autosomal recessive (MYH) Management Appropriately timed colectomy Surveillance of rectal segment every 6-12 months if subtotal colectomy Upper tract surveillance 1-3 years Duodenoscope in addition to regular EGD Biopsy even if endoscopically normal Chemoprevention largely used for rectal remnants and upper tract polyps No proven role for primary chemoprevention 2

3 Prenatal Genetic Testing in Patients With Clinical Features of HNPCC (Lynch Syndrome) Embryo Biopsy: Micromanipulations for PGD Prenatal testing is available for APC mutation carriers: -Amniocentesis -Chorionic villous sampling (CVS) -Preimplantation genetic diagnosis (PGD) Can reveal whether an embryo or fetus is affected with Early but variable age at diagnosis (~45 years) Multiple primary cancers Tumor site in proximal colon predominates Extracolonic cancers: endometrium, ovary, stomach, urinary tract, small bowel, bile ducts, sebaceous skin tumors Prenatal counseling is part of care of APC mutation carriers HNPCC Results From Failure of Mismatch Repair (MMR) Genes Base pair mismatch T C T A C Normal DNA repair T C G A C A G C T G A G C T G Reproduced with permission from parents Defective DNA repair (MMR+) T C T A C A G C T G T C T A C A G A T G Case B 35 year old with cecal carcinoma and no other polyps. Family history is notable for mother with endometrial cancer at age 50. Mismatch Repair Failure Leads to Microsatellite Instability (MSI) Normal Is there a genetic predisposition to cancer? What are the primary diagnostic considerations? Would you recommend any tumor-based testing or proceed directly to germline testing? Which genes would you test for? When would you recommend that he have his next colonoscopy? Microsatellite instability Addition of nucleotide repeats 3

4 Contribution of Gene Mutations to HNPCC Families Unknown ~20% MSH6 ~ 10% PMS2 ~ 10% MSH2 ~30% MLH1 ~30% Mutation in gene leads to loss of protein expression that can be detected by IHC risk assessment can be complicated Mother diagnosed with endometrial cancer at age 50 Aunt diagnosed with ovarian cancer at age 49 Grandmother and uncle with renal cell CA (75,41) Cousin with colon cancer at a young age Surveillance for Lynch Syndrome Malignancy Colorectal cancer Endometrial cancer Intervention Colonoscopy Transvaginal ultrasound Endometrial aspirate Cancer Genetics Studies Consortium Task Force Recommendations Modified from Burke W et al. JAMA 277:915, 1997 Recommendation Begin at age 20 25, 25, repeat every 1 21 years Annually, starting at age Family history assessment in clinical practice Often not comprehensive Often does not address ages at diagnosis Frequently limited to first-degree relatives Restricted to include only certain cancer types e.g. Any history of colon cancer in your family? Relationship between different cancers (e.g. colon and endometrial CA) may be missed Grover et al CGH 2004; Murff et al. Am J Prevent Med 2004; Singh et al. CGH 2010 Prophylactic Surgery Options for Lynch Syndrome Colon cancer options include subtotal colectomy vs total colectomy Uterine and ovarian cancer options include hysterectomy and oophorectomy Individual patient decision dependent on compliance with screening, efficacy of screening tests, need for surgical resection *Burke et al. JAMA :915 Syngal et al. Ann Intern Med :787 Schmeler et al. NEJM 2006 The Pre-procedural Colorectal Cancer Risk Assessment Tool (CRAT) Do you have a first-degree relative (mother, father, brother, sister or child) YES NO with any of the following conditions diagnosed before age 50? Colon or rectal cancer Cancer of the uterus, ovary, stomach, small intestine, urinary tract (kidney, ureter, bladder), bile ducts, pancreas, or brain Have you had any of the following conditions diagnosed before age 50? Colon or rectal cancer Colon or rectal polyps Do you have 3 or more relatives with a history of colon or rectal cancer? (this includes parents, brothers, sisters, children, grandparents, aunts, uncles and cousins) Kastrinos et al. Am J Gastro 2009:104(6):

5 Prediction of MLH1/MSH2/MSH6 Mutations (PREMM 1,2,6 ) Model 1. Proband history l Presence of colon cancer, other HNPCC cancer and/or adenomas l Age of onset 2. Family history l Presence of colon or other HNPCC cancer l Youngest age at diagnosis Predicted probability of mutation in MLH1/MSH2/MSH6 Kastrinos et al. Gastro 2010 How to systematize family history in your practices Implement CRAT in endoscopy or clinic practices (add question: have you had more than 10 polyps) If yes to ANY question, needs further detailed history Kastrinos et al. Am J Gastro 2009:104(6): Possible Lynch Syndrome Patient Generate PREMM model estimate If PREMM >5%, needs molecular evaluation MSI and/or IHC Testing if tumor blocks exist Direct germline testing for MLH1, MSH2, MSH6 +/- PMS2 if no block or if MSI/IHC abnormal Balmana et al. JAMA 2006; Kastrinos et al. Gastro 2010 PREMM 1,2,6 Estimates PREMM 1,2,6 Estimates: Patient >10 Polyps EC 45y 61y EC 70y + MSH6 EC 51y Any MMR mutation 47.3% MLH1 mutation 7.6% MSH2 mutation 15.1% MSH6 mutation 24.6% Unless predominantly hyperplastic, needs path review, EGD, and close follow-up. If more than 20 adenomas MYH and APC testing If predominantly hamartomas, consider specific syndrome Kastrinos et al, Gastro 2010, in press 5

6 Take-home messages Risk stratification is key in deciding tests of choice and screening intervals We need to systematically obtain accurate family histories from our patients Genetics and molecular evaluation of patients is part of standard of care Think genetics if: Too many (in same person or family members) Too big or too weird Too young (cancer <50, adenoma <40) 6