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

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 (%) All Races5.882.57 Whites5.992.63 Blacks4.422.14 Male + Female LR DxLR Death SEER, 1992 - 4

5. Etiologic Concepts in CRC

6. Colorectal Cancer 1%

7. Click for larger picture

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

9. Polymorphisms and CRC Risk Low penetrance susceptibility alleles- Meta Analysis APC I1307K1.6 (1.2 - 2.1) HRAS1-VNTR2.5 (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 OR

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 Study NHS & 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 1 o relative = mother, father, sibs Fuchs et al; NEJM 1994;331:1669-74

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

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

16. Germline Mutations

19. Gastro 2001;121:195

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

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

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

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

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