1. Lecture 22 Cancer Genetics II: Inherited Susceptibility to Cancer Stephen B. Gruber, MD, PhD November 19, 2002

2. Cancer Genetics: II Summary Inherited susceptibility to cancer due to germline mutations Causes of inherited susceptibility to colorectal cancer Familial Adenomatous Polyposis Hereditary Non-Polyposis Colorectal Cancer

3. Causes of Hereditary Susceptibility to CRC Adapted from Burt RW et al. Prevention and Early Detection of CRC, 1996 Sporadic (65 %– 85%) Familial (10 %– 30%) Hereditary nonpolyposis colorectal cancer (HNPCC) (5%) Familial adenomatous polyposis (FAP) (1%) Rare CRC syndromes (<0.1%)

4. Multi-Step Carcinogenesis NormalepitheliumHyper-proliferativeepitheliumEarlyadenomaLateadenomaCarcinomaMetastasis Loss of APCActivation of K-ras Loss of 18q TP53Otheralterations Adapted from Fearon ER. Cell 61:759, 1990 Inter-mediateadenoma ASCO

5. Risk of Colorectal Cancer (CRC) 020406080100 General population Personal history of colorectal neoplasia Inflammatory bowel disease HNPCC mutation FAP 6% 15%–20% 15%–40% 70%–80% >95% Lifetime risk (%)

6. Clinical Features of FAP Estimated penetrance for adenomas >90% Risk of extracolonic tumors (upper GI, desmoid, osteoma, thyroid, brain, other) CHRPE may be present Untreated polyposis leads to 100% risk of cancer ASCO

7. Some FAP Manifestations Correlate With Specific APC Gene Regions Attenuated FAP Classic FAP CHRPE 12 3 456 7 8910 11 1213 14 155'3'

8. Attenuated FAP ASCO Later onset (CRC ~age 50)Later onset (CRC ~age 50) Fewer colonic adenomasFewer colonic adenomas Not associated with CHRPENot associated with CHRPE UGI lesionsUGI lesions Associated with mutations at 5' and 3' ends of APC geneAssociated with mutations at 5' and 3' ends of APC gene

9. Clinical Features of HNPCC Early but variable age at CRC diagnosis (~45 years) Tumor site in proximal colon predominates Extracolonic cancers: endometrium, ovary, stomach, urinary tract, small bowel, bile ducts, sebaceous skin tumors

10. Amsterdam Criteria l 3 or more relatives with verified CRC in family - One case a first-degree relative of the other two - One case a first-degree relative of the other two l 2 or more generations l 1 CRC by age 50 l FAP excluded Vasen HFA et al. Dis Colon Rect 34:424, 1991 Failure to meet these criteria does not exclude HNPCC

11. Genetic Features of HNPCC Autosomal dominant inheritance Penetrance ~80% Genes belong to DNA mismatch repair (MMR) family Genetic heterogeneity (MLH1, MSH2, MSH6, PMS1, PMS2)

12. Genetic Heterogeneity in HNPCC HNPCC is associated with germline mutations in any one of at least five genes Chr 2 Chr 3 Chr 7 MSH2 PMS1 MLH1 PMS2 MSH6

13. Contribution of Gene Mutations to HNPCC Families MSH2 ~30% MLH1~30% PMS1 (rare) PMS2 (rare) MSH6 (rare) Unknown ~30% SporadicFamilial HNPCC FAP Rare CRC syndromes Liu B et al. Nat Med 2:169, 1996

14. Cancer Risks in HNPCC Aarnio M et al. Int J Cancer 64:430, 1995 % with cancer 100 80 60 40 20 0 204060800 Age (years) Colorectal 78% Endometrial 43% Stomach 19% Biliary tract 18% Urinary tract 10% Ovarian 9% ASCO

15. HNPCC Results From Failure of Mismatch Repair (MMR) Genes Base pair mismatch Normal DNA repair Defective DNA repair (MMR+) T CTA C A G C T G T C G A C A G C T G T CTA C A G A T G T C T A C

16. Structure of Mismatch Repair Obmolova G, Nature 407;703, 2000 Lamers et al, Nature 407;711, 2000

17. Mismatch Repair Failure Leads to Microsatellite Instability (MSI) Normal Microsatellite instability Addition of nucleotide repeats

18. NEJM 342:71, 2000 Microsatellite Instability (MSI) 10%–15% of sporadic tumors have MSI10%–15% of sporadic tumors have MSI 95% of HNPCC tumors have MSI at multiple loci95% of HNPCC tumors have MSI at multiple loci

19. Surveillance Options for Carriers of HNPCC-Associated Mutations Cancer Genetics Studies Consortium Task Force Recommendations Modified from Burke W et al. JAMA 277:915, 1997 InterventionColonoscopy Transvaginal ultrasound Transvaginal ultrasound Endometrial aspirate Endometrial aspirateRecommendation Begin at age 20–25, repeat every 1–2 years Annually, starting at age 25–35 Malignancy Colorectal cancer Endometrial cancer

20. Surveillance Reduces Risk of Colorectal Cancer in HNPCC Families Jarvinen HJ et al. Gastro 108:1405, 1995 % of subjects with CRC 30 20 10 4.5% 11.9% 0369 Years of follow-up Surveillance No surveillance 0 ASCO

21. Surveillance Improves HNPCC Survival 9 0.6 0.7 0.8 0.9 1.0 0.5 3612150 Jarvinen H et al Gastroenterology 118;829, 2000 Years of follow-up Survival 65% reduction in mortality p = 0.05 Surveillance No surveillance

22. Cancer Genetics: II Summary Inherited susceptibility to cancer due to germline mutations Familial Adenomatous Polyposis Hereditary Non-Polyposis Colorectal Cancer –Amsterdam criteria Surveillance reduces the risk of cancer Genetic counseling / testing plays an important role in the management of families with inherited susceptibility to cancer

23. Special thanks to David Barrett Please check out his latest CD, “It’s a long, long story” www.DavidBarrett.com or in concert at the Greenwood Café Acoustic Series December 6, 7:30pm www.DavidBarrett.com