Variation in TCF7L2 and Increased Risk of Colon Cancer: The Atherosclerosis Risk in Communities (ARIC) Study

Abstract

OBJECTIVE: To determine whether variation in the transcription factor 7-like 2 (TCF7L2) gene, which influences diabetes risk, is associated with incidence of cancers.

RESEARCH DESIGN AND METHODS: We related diabetes and TCF7L2 variation with occurrence of several common cancers in a prospective cohort study of 13,117 middle-aged adults initially free of cancer in 1987–89. We assessed five SNPs in TCF7L2 including the putative SNP (rs7903146) for diabetes. We identified incident cancers through 2000 via cancer registries, supplemented by hospital records.

RESULTS: Diabetes was associated marginally inversely with incidence of prostate cancer, but not associated with incidence of colorectal, colon, lung, or breast cancer. The T allele of rs7903146 (frequency = 30%) was associated with increased risk of colorectal cancer and, more specifically, colon cancer, with adjusted hazard ratios (95% CI) of 1.0 for CC, 1.25 (0.85, 1.83) for CT, and 2.15 (1.27, 3.64) for TT genotypes (p for trend = 0.009). TCF7L2 variation also was associated with lung cancer incidence in whites but not blacks, but residual confounding by smoking may be present.

CONCLUSIONS: Initially cancer-free subjects carrying certain genetic variants of TCF7L2, most notably the T allele of rs7903146, have increased risk of colon cancer. This association appears to be an independent gene effect, not explained by diabetes. Because the T allele of rs7903146 is common, if a causal link is established, this variant could account for a sizable proportion (approximately 17% here) of colon cancer cases in the general population.