1 / 23

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

sasha
Télécharger la présentation

Lecture 22 Cancer Genetics II: Inherited Susceptibility to Cancer

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

  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

More Related