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    • 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
      • Hereditary Non-Polyposis Colorectal Cancer
    • 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%)
    • Multi-Step Carcinogenesis Normal epithelium Hyper- proliferative epithelium Early adenoma Late adenoma Carcinoma Metastasis Loss of APC Activation of K-ras Loss of 18q Loss of TP53 Other alterations Adapted from Fearon ER. Cell 61:759, 1990 Inter- mediate adenoma ASCO
    • Risk of Colorectal Cancer (CRC) 0 20 40 60 80 100 General population Personal history of colorectal neoplasia Inflammatory bowel disease HNPCC mutation FAP 6% 15%–20% 15%–40% 70%–80% >95% Lifetime risk (%)
    • 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
    • Some FAP Manifestations Correlate With Specific APC Gene Regions Attenuated FAP Classic FAP CHRPE 5' 3' 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15
    • Attenuated FAP ASCO
      • 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
    • 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
    • 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
      Vasen HFA et al. Dis Colon Rect 34:424, 1991 Failure to meet these criteria does not exclude HNPCC
    • Genetic Features of HNPCC
      • Autosomal dominant inheritance
      • Penetrance ~80%
      • Genes belong to DNA mismatch repair (MMR) family
      • Genetic heterogeneity ( MLH1, MSH2, MSH6, PMS1, PMS2 )
    • 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
    • Contribution of Gene Mutations to HNPCC Families MSH2 ~30% MLH1 ~30% PMS1 (rare) PMS2 (rare) MSH6 (rare) Unknown ~30% Sporadic Familial HNPCC FAP Rare CRC syndromes Liu B et al. Nat Med 2:169, 1996
    • Cancer Risks in HNPCC Aarnio M et al. Int J Cancer 64:430, 1995 % with cancer 100 80 60 40 20 0 20 40 60 80 0 Age (years) Colorectal 78% Endometrial 43% Stomach 19% Biliary tract 18% Urinary tract 10% Ovarian 9% ASCO
    • HNPCC Results From Failure of Mismatch Repair (MMR) Genes Base pair mismatch Normal DNA repair Defective DNA repair (MMR+) T C T A C A G C T G T C G A C A G C T G T C T A C A G C T G A G A T G T C T A C
    • Structure of Mismatch Repair Obmolova G, Nature 407;703, 2000 Lamers et al, Nature 407;711, 2000
    • Mismatch Repair Failure Leads to Microsatellite Instability (MSI) Normal Microsatellite instability Addition of nucleotide repeats
    • Microsatellite Instability (MSI) NEJM 342:71, 2000
      • 10%–15% of sporadic tumors have MSI
      • 95% of HNPCC tumors have MSI at multiple loci
    • 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
      • Intervention
      • Colonoscopy
      • Transvaginal ultrasound
      • Endometrial aspirate
      Recommendation Begin at age 20–25, repeat every 1–2 years Annually, starting at age 25–35 Malignancy Colorectal cancer Endometrial cancer
    • 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% 0 3 6 9 Years of follow-up Surveillance No surveillance 0 ASCO
    • Surveillance Improves HNPCC Survival 9 0.6 0.7 0.8 0.9 1.0 0.5 3 6 12 15 0 Jarvinen H et al Gastroenterology 118;829, 2000 Years of follow-up Survival 65% reduction in mortality p = 0.05 Surveillance No surveillance
    • 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
    • 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