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
Whites
Blacks
SEER,

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 ( )
HRAS1-VNTR ( )
MTHFR (val/val) ( )
P53, NAT1, NAT2, GSTM1, GSTT1, GSTP1
exclude >1.7 fold increase
Houlston, Gastro 2001;121:282

10. TCE: Colonoscopy or DCBE + FS
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
1o relative = mother, father, sibs
Fuchs et al; NEJM 1994;331:

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:

14. Family Hx - Prospective Study NHS & 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

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 1o 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 1o Relative of other 2
• 2 successive generations (at least)
• 1 diagnosed before age 50
FAP excluded
Verify Tumors