Interaction of TCF7l2 with translocated β-catenin in the nucleus transiently converts TCF7L2 to transcription factor activators, which induce the expression of target genes, including cyclin D1 and c-myc, in colorectal carcinogenesis. We evaluated the association of a polymorphism in TCF7L2 (RS12255372) which previously has been strongly associated with risk of Type II Diabetes, with colorectal cancer (CRC) and adenoma in the prospective Nurses’ Health Study (NHS) and Health Professionals Follow-up Study (HPFS) cohorts. In the NHS and HPFS control populations, the TCF7L2 T-allele frequency ranged from 28 to 30% and the genotype distribution was in agreement with Hardy-Weinberg equilibrium. Overall, there was suggestive evidence for an inverse association associated with homozygosity for the minor allele of RS12255372 (TCF7L2 TT) and CRC (conditional and covariate adjusted OR=0.63, 95%CI: 0.37–1.08; P for heterogeneity 0.52 for the association in women and men), which was more evident among women (OR=0.39, 95%CI: 0.16 – 0.91). The polymorphism was not associated with risk of colorectal adenoma. Furthermore, we observed no evidence of effect modification between the TCF7L2 SNP and covariates such as family history (p-interaction=0.45) or BMI (p-interaction=0.27) or with genetic variants in the APC Asp1822Val SNP (NHS cancer p-interaction=0.40, NHS adenoma p-interaction 0.10). In summary, the marginal association of TCF7L2 SNP with CRC may be due to chance, but warrants further laboratory and epidemiological investigation.
Keywords: TCF7L2, polymorphism, Wnt pathway, colorectal cancer