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Hereditary Colorectal Cancer: From Genetic Testing to Prevention

Hereditary Colorectal Cancer: From Genetic Testing to Prevention. Robert E. Schoen, MD MPH Associate Professor of Medicine and Epidemiology Division of Gastroenterology University of Pittsburgh. Colorectal Cancer - Epidemiology. 2nd leading cause of CA mortality in U.S.

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Hereditary Colorectal Cancer: From Genetic Testing to Prevention

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  1. Hereditary Colorectal Cancer: From Genetic Testing to Prevention Robert E. Schoen, MD MPH Associate Professor of Medicine and Epidemiology Division of Gastroenterology University of Pittsburgh

  2. Colorectal Cancer - Epidemiology • 2nd leading cause of CA mortality in U.S. • > 130,000 new cases/yr • > 48,000 deaths/yr

  3. Estimated Cancer Deaths in U.S. - 1999 Men Women Lung - 31% Lung - 25% Prostate - 13% Breast - 16% Colorectal - 10% Colorectal - 11%

  4. Lifetime Risk of CRC (%) Male + Female LR Dx LR Death All Races 5.88 2.57 Whites 5.99 2.63 Blacks 4.42 2.14 SEER, 1992 - 4

  5. Etiologic Concepts in CRC

  6. Colorectal Cancer 1%

  7. Click for larger picture

  8. Intermediate Endpoint Environment Alteration in Large Bowel Epithelium Cancer Host

  9. Polymorphisms and CRC Risk Low penetrance susceptibility alleles- Meta Analysis OR APC I1307K 1.6 (1.2 - 2.1) HRAS1-VNTR 2.5 (1.5 - 4.1) MTHFR (val/val) 0.8 (0.6 - 0.9) P53, NAT1, NAT2, GSTM1, GSTT1, GSTP1 exclude >1.7 fold increase Houlston, Gastro 2001;121:282

  10. Consensus Guidelines > = 50  Options:  Annual FOBT  FS q 5 yrs  FOBT + FS  DCBE q 5-10 yr  Colon q 10 yr  + TCE: Colonoscopy or DCBE + FS Gastro. 1997:112;594

  11. Familial CRC

  12. Family Hx - Prospective StudyNHS & HPFS (1) 87,000 women; 32,000 men 315 and 148 cases CRC RR = Incidence CRC with fm hx* CRC Incidence CRC with NO fm hx CRC 1o relative = mother, father, sibs Fuchs et al; NEJM 1994;331:1669-74

  13. Family Hx - Prospective StudyNHS & HPFS (2) Family Hx CRC reported by 10% of sample RR CRC with Fm Hx = 1.7* * adjusted for diet, ASA, physical activity, cigs, screening endoscopy Fuchs et al; NEJM 1994;331:1669-74

  14. Family Hx - Prospective StudyNHS & HPFS (3) Conclusions: • Risk with 2 or more 1o relatives •  Risk with family member  55

  15. AHCPR Guidelines Family Hx • CRC in 1 or 2 (?) FDR • Adenomas in FD relative  60 Same Options as Avg Risk, but Start at age 40 Gastro 1997:112;594

  16. Germline Mutations

  17. Gastro 2001;121:195

  18. HNPCC - Clinical Characteristics • Autosomal dominant, highly penetrant • CRC <age 45,  synchro/proximal • Polyps - larger, more aggressive; cancers better prognosis • Endometrial, ovarian, other CA’s

  19. HNPCC Recognition • Early onset cancers • Multiple cancers in successive generations • Association with other cancers - endometrial

  20. HNPCC - “Amsterdam Criteria” • Three or more relatives with CRC, one of whom is 1o relative of other two • CRC in at lest 2 generations • One or more cases before age 50

  21. Amsterdam Criteria II 3 Relatives with HNPCC associated CA: CRC, Endometrial, Small Bowel Ureter, Renal Pelvis • 1 should be 1o Relative of other 2 • 2 successive generations (at least) • 1 diagnosed before age 50 FAP excluded Verify Tumors

  22. CRC@40 CRC@56 Endomet @48 CRC@45 CRC@68 CRC@48

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