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 A allele 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. Impact: If this finding is supported by further replication and functional studies, it may highlight new pathways underlying colorectal neoplasia. Cancer Epidemiol Biomarkers Prev; 19(12); 3131-9. (C) 2010 AACR.