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Variation in TCF7L2 and Increased Risk of Colon Cancer

The Atherosclerosis Risk in Communities (ARIC) Study

¹ Division of Epidemiology & Community Health, School of Public Health, University of Minnesota, Minneapolis, Minnesota
² Department of Epidemiology, School of Public Health, University of North Carolina, Chapel Hill, North Carolina
³ Human Genetics Center and Institute of Molecular Medicine, University of Texas Health Science Center, Houston, Texas

Address correspondence and reprint requests to Aaron R. Folsom, MD, Division of Epidemiology & Community Health, School of Public Health, University of Minnesota, Suite 300, 1300 S. Second St., Minneapolis, MN 55454-1015. E-mail: folsom{at}epi.umn.edu

OBJECTIVE—The purpose of this study was to determine whether a 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 1987–1989. We assessed five single nucleotide polymorphisms (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 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_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—Subjects who were initially cancer-free and carrying certain genetic variants of TCF7L2, most notably the T allele of rs7903146, have an 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 (17% here) of cases of colon cancer in the general population.

Abbreviations: APC, adenomatous polyposis coli • ARIC, Atherosclerosis Risk in Communities • SNP, single nucleotide polymorphism • TCF7L2, transcription factor 7-like 2

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