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Mechanisms and Epidemiology of Colon Cancer

Mechanisms and Epidemiology of Colon Cancer. Anil K. Rustgi, MD University of Pennsylvania. Worldwide Statistics for Colorectal Cancer (CRC). Estimated 875,000 cases in 1996  8.5% of all new cases of cancer Incidence rates vary by ~20-fold

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Mechanisms and Epidemiology of Colon Cancer

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  1. Mechanisms and Epidemiology of Colon Cancer Anil K. Rustgi, MD University of Pennsylvania

  2. Worldwide Statistics for Colorectal Cancer (CRC) • Estimated 875,000 cases in 1996 •  8.5% of all new cases of cancer • Incidence rates vary by ~20-fold •  highest in North America, Western Europe, • Australia, New Zealand, Japan •  lowest in India, Northern Africa • Estimated deaths for 1998: 556,000

  3. Estimated New Cancer Cases of 10 Leading Sites by Gender for the US 2000

  4. Colorectal Cancer Statistics in the US • Second overall leading cause of cancer-related deaths in the US • Estimated 130,000 new cases and 56,300 deaths in the year 2000 • Declining trends between 1990 and 1996 • Incidence reate: ~2.1% per year • Mortality rates: ~1.7% per year

  5. Average Annual Age-Specific US Incidence and Mortality Rates of CRC, 1992-1996

  6. Risk Factors for Colorectal Cancer (CRC) • Aging • Personal history of CRC or adenomas • High-fat, low-fiber diet • Inflammatory bowel disease • Family history of CRC • Hereditary colon cancer syndromes

  7. Risk of Colorectal Cancer (CRC) 5% 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 (%)

  8. Familial Risk for Colorectal Cancer 70% Approximate lifetime CRC risk (%) 17% 10% 8% 6% 2% One 1° and two 2° One 1° age <45 HNPCC mutation None One 1° Two 1° Aarnio M et al. Int J Cancer 64:430, 1995 Houlston RS et al. Br Med J 301:366, 1990 St John DJ et al. Ann Intern Med 118:785, 1993 Affected family members

  9. 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

  10. 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

  11. Genetics of FAP • Autosomal dominant inheritance • Caused by mutations in APC tumor suppressor gene on chromosome 5q • Up to 30% of patients have de novo germline mutations • Most families have unique mutations • Most mutations are protein truncating • Genotype/phenotype relationships emerging

  12. 15 3 7 14 1 2 4 5 6 8 9 10 12 13 11 The APC Tumor Suppressor Gene Codon 1309 5' 3'

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

  14. Indications for APC Gene Testing • Molecular diagnosis of FAP in patients who present with: • polyposis (>100 adenomas) • attenuated FAP • Predictive testing for FAP in blood relatives of persons with FAP or known APC mutations Giardiello FM et al. N Engl J Med, 336:823, 1997

  15. 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

  16. Amsterdam Criteria • 3 or more relatives with verified CRC in family • One case a first-degree relative of the other two • Two or more generations • One 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

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

  18. 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

  19. 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

  20. Microsatellite Instability (MSI) • 10%–15% of sporadic tumors have MSI • 95% of HNPCC tumors have MSI at multiple loci • Routine MSI assays soon available Normal MSI tumor Electrophoresis gel

  21. Genetic Testing for HNPCC Susceptibility Begin genetic testing with affected family member Positive result Negative result Continued risk of unidentified familial mutation Offer testing to at-risk family members

  22. Features of Familial CRC • Family history of CRC with no clear inheritance pattern • Age at onset typical of sporadic CRC • Multiple causes • Few or no adenomas Sporadic Familial CRC FAP HNPCC Rare CRC syndromes

  23. Mouse Models of Colon Cancer • Apc (Min) • Smad • DNA mismatch repair • Ras

  24. Loss of APC Activation of K-ras Deletion 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

  25. Adenomatous polyp • Adenomatous polyp • Can take 5-10 years for polyp to develop • Up to 10% of polyps develop into cancer • Size and histology are risk factors for polyp to cancer progression

  26. Surrogate Markers for Chemoprevention • Polyp (size/number) • Mouse models, FAP/HNPCC, General population (sporadic) • Biomarkers (mucosa/polyp) • Proliferation • Differentiation • Apoptosis • Gene arrays (functional genomics) • Biomarkers (stool/blood) • Investigational

  27. Summary • Risk factors for colon cancer • Inherited • Acquired (sporadic)-adenomatous polyp, IBD • Genetic basis for colon cancer • Inherited (FAP, HNPCC, to be defined) • Sporadic polyp-different pathways • Preclinical models for colon cancer

  28. Summary (continued) Applications of chemoprevention initially in animal models and inherited forms of colon cancer, and then to general population Determine efficacy of chemoprevention with surrogate markers

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