Hereditary Colorectal Cancer: From Genetic Testing to Prevention

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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
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Colorectal Cancer - Epidemiology

• 2nd leading cause of CA mortality in U.S.
• gt 130,000 new cases/yr
• gt 48,000 deaths/yr

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Estimated Cancer Deaths in U.S. - 1999
Men Women Lung - 31 Lung -
25 Prostate - 13 Breast - 16 Colorectal -
10 Colorectal - 11
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Lifetime Risk of CRC ()
Male Female
LR Dx
LR Death
All Races 5.88 2.57 Whites 5.99 2.63 Black
s 4.42 2.14
SEER, 1992 - 4
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Etiologic Concepts in CRC
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Colorectal Cancer
1
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Click for larger picture
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Intermediate Endpoint
Environment
Alteration in Large Bowel Epithelium
Cancer
Host
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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 gt1.7
fold increase
Houlston, Gastro 2001121282
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Consensus Guidelines

gt 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. 1997112594
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Familial CRC
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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 19943311669-74
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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 19943311669-74
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Family Hx - Prospective StudyNHS HPFS (3)
Conclusions
?? Risk with 2 or more 1o relatives ?? Risk
with family member ? 55
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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 1997112594
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Germline Mutations
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Gastro 2001121195
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HNPCC - Clinical Characteristics
Autosomal dominant, highly penetrant CRC
ltage 45, ? synchro/proximal Polyps - larger,
more aggressive cancers better prognosis
Endometrial, ovarian, other CAs
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HNPCC Recognition
Early onset cancers Multiple cancers in
successive generations Association with other
cancers - endometrial
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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
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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
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CRC_at_40
CRC_at_56 Endomet _at_48
CRC_at_45
CRC_at_68
CRC_at_48