Characterization of 9p24 risk locus and colorectal adenoma and cancer: gene-environment interaction and meta-analysis.
BACKGROUND
A potential susceptibility locus for colorectal cancer on chromosome 9p24 (rs719725) was initially identified through a genome-wide association study, though replication attempts have been inconclusive.


METHODS
We genotyped this locus and explored interactions with known risk factors as potential sources of heterogeneity, which may explain the previously inconsistent replication. We included Caucasians with colorectal adenoma or colorectal cancer and controls from 4 studies (total 3,891 cases, 4,490 controls): the Women's Health Initiative (WHI); the Diet, Activity and Lifestyle Study (DALS); a Minnesota population-based case-control study (MinnCCS); and the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial (PLCO). We used logistic regression to evaluate the association and test for gene-environment interactions.


RESULTS
SNP rs719725 was statistically significantly associated with risk of colorectal cancer in WHI (OR per A allele 1.19; 95% CI, 1.01-1.40; P(trend) = 0.04), marginally associated with adenoma risk in PLCO (OR per A allele 1.11; 95% CI, 0.99-1.25; P(trend) = 0.07), and not associated in DALS and MinnCCS. Evaluating for gene-environment interactions yielded no consistent results across the studies. A meta-analysis of 17 studies (including these 4) gave an OR per A allele of 1.07 (95% CI, 1.03-1.12; P(trend) = 0.001).


CONCLUSIONS
Our results suggest the Aallele for SNP rs719725 at locus 9p24 is positively associated with a small increase in risk for colorectal tumors. Environmental risk factors for colorectal cancer do not appear to explain heterogeneity across studies.


CONCLUSIONS
If this finding is supported by further replication and functional studies, it may highlight new pathways underlying colorectal neoplasia.
Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington 98109, USA.
Jonathan D
JD
Kocarnik
Carolyn M
CM
Hutter
Martha L
ML
Slattery
Sonja I
SI
Berndt
Li
L
Hsu
David J
DJ
Duggan
Jill
J
Muehling
Bette J
BJ
Caan
Shirley A A
SA
Beresford
Aleksandar
A
Rajkovic
Gloria E
GE
Sarto
James R
JR
Marshall
Nazik
N
Hammad
Robert B
RB
Wallace
Karen W
KW
Makar
Ross L
RL
Prentice
John D
JD
Potter
Richard B
RB
Hayes
Ulrike
U
Peters
D000236:Adenoma / Q000235:genetics*; D000368:Aged; D002899:Chromosomes, Human, Pair 9 / Q000235:genetics*; D015179:Colorectal Neoplasms / Q000235:genetics*; D005260:Female; D056426:Genetic Loci; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D012307:Risk Factors