1. Hereditary Colorectal Cancer: An Overview Felice Schnoll-Sussman,MD Jay Monahan Center for Gastrointestinal Health New York Hospital/ Weill Cornell Medical College

2. U.S. Cancer Cases and Deaths - 2001 CA Ca J Clin 2001

3. Colon Cancer, 2001 135,400 cases, 56,700 deaths 135,400 cases, 56,700 deaths 2 nd most common cause of cancer death 2 nd most common cause of cancer death Lifetime risk 6%, about 1 in 17 Lifetime risk 6%, about 1 in 17 93% of cases occur at >50 years age 93% of cases occur at >50 years age

4. Colon Cancer Arises from Polyps Small Polyp Large Polyp Cancer

5. Characteristics of Screening Tests for CRC

6. Sporadic cases Other inherited cases, 32% Hamar- tomatous polyposis, <1% FAP, <1% HNPCC, 1%-3% Inherited Colon Cancer Cannon-Albright, N Engl J Med 1988; 319:533 Lichtenstein N Engl J Med 2000; 343:78

7. Syndromes Genes SyndromeGene FAPAPC HNPCCMMR Peutz-JeghersSTK11 Juvenile PolyposisSMAD4 Cowden SyndromePTEN

8. Hereditary Mother or Father 1 damaged gene 1 normal gene Nonhereditary 2 normal genes Loss of normal gene 1 damaged gene 1 normal gene Loss of normal gene 1 damaged gene 1 normal gene The Development of Hereditary Cancer © 2001 Myriad Genetic Laboratories

9. Malignant transformation TCGAT AGCTA HNPCC results from defective DNA repair AGCTA TCGAT AGCTA TCGAT Cell with DNA mismatch repair AG T TA TC A AT Cell without DNA mismatch repair (HNPCC) AG T TA TC G AT

10. Genes That Give Rise to HNPCC HNPCC is associated with germline mutations in any one of five mismatch repair genes Chr 2 Chr 3 Chr 7 MSH2 PMS1 MLH1 PMS2 MSH6

11. Population Risk By age 50 0.2% By age 70 2% HNPCC Risk >25%80% Gastroenterology 1996;110:1020-7 Int J Cancer 1999;81:214-8 HNPCC Increases the Risk of Colorectal Cancer

12. Population Risk By age 50 0.2% By age 70 1.5% HNPCC Risk 20%60% Gastroenterology 1996;110:1020-7 Int J Cancer 1999;81:214-8 HNPCC Increases the Risk of Endometrial Cancer

13. HNPCC Increases the Risks of Other Cancers Ovary Ovary 12% by age 70 12% by age 70 Stomach Stomach 13% by age 70 13% by age 70 Other Other Urinary tract (4% by age 70) Urinary tract (4% by age 70) Small intestine (100-fold relative risk, but < 5%) Small intestine (100-fold relative risk, but < 5%) Biliary tract (2% by age 70) Biliary tract (2% by age 70) Brain (~4% by age 70) Brain (~4% by age 70) Gastroenterology 1996;110: 1020-7 Int J Cancer 1999;81:214-8

14. Cancer 1977;40:1849 Dis Colon Rectum 1993;36:388 HNPCC Increases the Risk of a Second Cancer

15. Features of HNPCC Sporadic Personal or family history of colorectal or endometrial cancer before age 50 Personal or family history of colorectal or endometrial cancer before age 50 Multiple cancers in an individual Multiple cancers in an individual Multiple generations affected Multiple generations affected Other tumors associated with HNPCC: ovarian, upper GI, renal pelvis, brain Other tumors associated with HNPCC: ovarian, upper GI, renal pelvis, brain Hereditary Family history of colorectal cancer but not other cancers associated with HNPCC Family history of colorectal cancer but not other cancers associated with HNPCC Later age of onset Later age of onset No clear pattern on one side of the family or the other No clear pattern on one side of the family or the other CRC, 47 CRC, 42 & 51 Endo, 46 CRC, 53 CRC, 71 CRC, 63

16. Identifying patients with HNPCC Before genetic testing was available, HNPCC was identified through defined criteria (“Amsterdam criteria”). Before genetic testing was available, HNPCC was identified through defined criteria (“Amsterdam criteria”). 3 relatives with HNPCC-associated cancer 3 relatives with HNPCC-associated cancer one relative is a 1 st -degree relative of the other two one relative is a 1 st -degree relative of the other two at least two successive generations at least two successive generations at least one diagnosed < 50 yrs at least one diagnosed < 50 yrs Many people with mutation-proven HNPCC do not meet these criteria. Many people with mutation-proven HNPCC do not meet these criteria. J Med Genet 2000;37:641-5

17. Laboratory Testing for HNPCC Clinical laboratory testing is available Clinical laboratory testing is available Complete sequence analysis of the MLH1 and MSH2 genes (the “gold standard”) Complete sequence analysis of the MLH1 and MSH2 genes (the “gold standard”) Turnaround time of 3 weeks Turnaround time of 3 weeks Testing is available through health care providers Testing is available through health care providers For more information For more information 800-469-7423 (Myriad Genetic Laboratories) 800-469-7423 (Myriad Genetic Laboratories) www.colaris-hnpcc.com www.colaris-hnpcc.com

18. Microsatellite Instability (MSI) is a Feature of HNPCC MSI is a DNA abnormality present in >90% of HNPCC-associated colorectal cancers MSI is a DNA abnormality present in >90% of HNPCC-associated colorectal cancers MSI indicates an increased likelihood of HNPCC MSI indicates an increased likelihood of HNPCC MSI is not diagnostic of HNPCC; also seen in 15% of sporadic colorectal cancers MSI is not diagnostic of HNPCC; also seen in 15% of sporadic colorectal cancers MSI analysis requires access to slides of archival paraffin-embedded colorectal cancers MSI analysis requires access to slides of archival paraffin-embedded colorectal cancers Nat Med 1996;2:169-74

19. Overall Approach Go directly to mutation testing if: Go directly to mutation testing if: –Amsterdam criteria + –Patient has two HNPCC tumors –CRC patient has FDR with HNPCC tumor, and one of them diagnosed at age  50 years –CRC  50 years Start with MSI if: Start with MSI if: –CRC patient has any FDR with HNPCC tumor

20. The Importance of Genetic Diagnosis 50 Probability of cancer (%) 100 Age (Years) 305070 Family History (without testing) With mutation Without mutation Adapted with permission from Ponder B: Genetic Testing for Cancer Risk. Science 1997; 278:1050-4. Copyright 1997 American Association for the Advancement of Science Each child of a carrier has a 50-50 chance of being at increased risk (or not).

21. Managing the Cancer Risk of HNPCC Surveillance Surveillance –Colonoscopy every 1-3 years beginning age 20-25, annually after age 40 –Annual transvaginal ultrasound and endometrial aspiration beginning age 25-35 Surgery Surgery –Subtotal colectomy for colorectal cancer or advanced adenomas –Consideration of hysterectomy/salpingo-oophorectomy, especially at time of surgery for diagnosed colorectal cancer

22. Colonoscopy Improves Survival of Genetically-Confirmed HNPCC Gastroenterology 2000;118:829-34 Survival 80 60 0510 Follow-up time (years) 40 100 15 92.2%Surveillance 73.9% No surveillance

23. Benefits and Limitations of Genetic Testing for HNPCC Benefits Benefits Identification of HNPCC can lead to interventions that prevent cancer or detect it when it is still curable. Identification of HNPCC can lead to interventions that prevent cancer or detect it when it is still curable. Information for the health care of family members Information for the health care of family members Results can alleviate uncertainty and anxiety Results can alleviate uncertainty and anxiety Limitations Limitations A negative result is most informative if there is a known mutation in the family A negative result is most informative if there is a known mutation in the family Some genetic variants are of unknown clinical significance Some genetic variants are of unknown clinical significance

24. FAP About 1 in 10,000 births About 1 in 10,000 births Autosomal dominantly inherited Autosomal dominantly inherited 100’s to 1000’s of colonic adenomatous polyps 100’s to 1000’s of colonic adenomatous polyps Average age of polyp occurrence, 16 years Average age of polyp occurrence, 16 years

27. FAP, Colon Cancer Near 100% risk Near 100% risk Average age of diagnosis 39 yrs Average age of diagnosis 39 yrs 7% have colon cancer by age 21 7% have colon cancer by age 21 93% have colon cancer by age 50 93% have colon cancer by age 50

28. Other GI Polyps Gastric Gastric –At least 50% fundic gland polyps, rare cancer Duodenum Duodenum –>90% adenomatous polyps, 5%-10% cancer Small bowel Small bowel –About 50% adenomas, rare cancer

29. FAP, Extra-Colonic Cancers Life-time Risk(%)

30. The APC Tumor Suppressor Gene 3' 5' Codon 1309 12 3 456 7 8910 11 1213 14 15

31. FAP, Genetic Testing Methods used: Methods used: –Protein truncation test –Sequencing, with SSCP or DGGE –Linkage Mutation finding is 80% to 90% successful Mutation finding is 80% to 90% successful Once mutation found, relatives tested with near 100% accuracy Once mutation found, relatives tested with near 100% accuracy

32. FAP, Management Genetic testing Genetic testing Colonic screening Colonic screening –Annual sigmoidoscopy –Start at age 10 to 12 years –Colonoscopy for AAPC

33. FAP, Extra-Colonic Screening Duodenal: EGD every 1 to 3 years Duodenal: EGD every 1 to 3 years Pancreatic: ?Ultrasound, periodic Pancreatic: ?Ultrasound, periodic Thyroid: Annual exam Thyroid: Annual exam Gastric: EGD every 1 to 3 years Gastric: EGD every 1 to 3 years CNS: Annual H&P CNS: Annual H&P Liver: Ultrasound, AFP, annual <10 years Liver: Ultrasound, AFP, annual <10 years

34. “Genetic Discrimination” in Health Insurance is Illegal Health Insurance Portability and Accountability Act (HIPAA) Health Insurance Portability and Accountability Act (HIPAA) –Prohibits group health insurance plans from discriminating on the basis of genetic information. Most states have enacted additional protections Most states have enacted additional protections Family members do not have to disclose whether a relative has undergone genetic testing Family members do not have to disclose whether a relative has undergone genetic testing “Like so-called urban legends that are built on rumor rather than fact, the perception of insurance company bias against patients who undergo predictive genetic testing seems to be largely unsubstantiated.”- JAMA 1999;282:2197-8,