Genetic variation in the TGF-β signaling pathway and colon and rectal cancer risk

Abstract

Background: The TGF-β signaling pathway is an essential regulator of many cellular process involved in carcinogenesis. Smad proteins are central to the function of TGF-β signaling. In this study, we evaluated genetic variation in TGFβl, TGFβRl, Smadl, Smad2, Smad3, and Smad4 and risk of colon and rectal cancer. Methods: Data are from a large case-control study of colon (n = 1,444 cases, 1,841 controls) and rectal (n = 754 cases, 856 controls) cancer participants with DNA. Results: Both TGFβl rs1800469 and rs4803455 were associated with colon cancer [odds ratio (OR) = 0.65 and 1.43, 95% CI = 0.51-0.84 and 1.18-1.73, respectively) but not rectal cancer. Likewise, 1 of 3 tagSNPs for TGFβRl, 2 of the 4 tagSNPs for Smad2, and 4 of 37 Smad3 tagSNPs were associated with colon cancer. Fewer significant associations were observed for rectal cancer, with only 1 tagSNP in Smad2 and 3 tagSNP in Smad3 having 95% CIs excluding 1.0. Several Smad3 tagSNPs were only associated with CpG island methylator phenotype. We observed several statistically significant interactions between genetic variation in the TGF-β signaling pathway and NFκBl, further illustrating its involvement in proposed mechanisms. In addition, we observed statistically significant interaction between TGFβl, TGFβRl, and Smad3 and cigarette smoking, aspirin use, and estrogen status for both colon and rectal cancers. Variation in TGFβl, TGFβRl, and Smad3 seemed to influence survival after diagnosis of colon and rectal cancer. Conclusions: These findings provide further support for genetic variation in the TGF-β signaling pathway and risk of developing both colon and rectal cancers. ©2011 American Association for Cancer Research..