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Lecture 22 Cancer Genetics II: Inherited Susceptibility to Cancer

Lecture 22 Cancer Genetics II: Inherited Susceptibility to Cancer. Stephen B. Gruber, MD, PhD November 19, 2002. Cancer Genetics: II Summary. Inherited susceptibility to cancer due to germline mutations Causes of inherited susceptibility to colorectal cancer Familial Adenomatous Polyposis

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Lecture 22 Cancer Genetics II: Inherited Susceptibility to Cancer

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

  2. Cancer Genetics: IISummary • 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 Sporadic (65%–85%) Familial (10%–30%) Rare CRC syndromes (<0.1%) Hereditary nonpolyposis colorectal cancer (HNPCC) (5%) Familial adenomatous polyposis (FAP) (1%) Adapted from Burt RW et al. Prevention and Early Detection of CRC, 1996

  4. Multi-Step Carcinogenesis Loss of APC Activation of K-ras Loss of 18q Loss of TP53 Other alterations Normal epithelium Hyper- proliferative epithelium Early adenoma Inter- mediate adenoma Late adenoma Carcinoma Metastasis Adapted from Fearon ER. Cell 61:759, 1990 ASCO

  5. Risk of Colorectal Cancer (CRC) 6% General population Personal history of colorectal neoplasia 15%–20% Inflammatory bowel disease 15%–40% 70%–80% HNPCC mutation >95% FAP 0 20 40 60 80 100 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. 15 3 7 14 1 2 4 5 6 8 9 10 12 13 11 Some FAP Manifestations Correlate With Specific APC Gene Regions 5' 3' Attenuated FAP Classic FAP CHRPE

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

  9. 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 Clinical Features of HNPCC

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

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

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

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

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

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

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

  20. Surveillance Reduces Risk of Colorectal Cancer in HNPCC Families 30 Nosurveillance % of subjects with CRC Surveillance 20 11.9% 10 4.5% 0 0 3 6 9 Years of follow-up Jarvinen HJ et al. Gastro 108:1405, 1995 ASCO

  21. Surveillance Improves HNPCC Survival Surveillance 1.0 Nosurveillance 0.9 0.8 Survival 0.7 65% reduction in mortality p = 0.05 0.6 0.5 0 3 6 9 12 15 Years of follow-up Jarvinen H et al Gastroenterology 118;829, 2000

  22. Cancer Genetics: IISummary • 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 BarrettPlease check out his latest CD, “It’s a long, long story”www.DavidBarrett.comor in concert at the Greenwood Café Acoustic SeriesDecember 6, 7:30pm

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