Aspirin Use, 8q24 Single Nucleotide Polymorphism rs6983267, and Colorectal Cancer According to CTNNB1 Alterations

Abstract

Regular aspirin use reduces the risk for colorectal cancer (CRC), possibly through inhibition of WNT/cadherin-associated protein 1 (CTNNB1 or -catenin) signaling. The single nucleotide polymorphism (SNP) rs6983267 on chromosome 8q24 is a CRC susceptibility locus that affects binding activity of transcription factor 7 like-2 (TCF7L2) to CTNNB1, thereby altering expression of target oncogenes, including MYC.We evaluated regular aspirin use and CRC risk according to genotypes of SNP rs6983267 and CTNNB1 expression status in two prospective casecontrol studies (840 CRC case patients and 1686 age- and race-matched control subjects) nested within the Nurses Health Study and the Health Professionals Follow-up Study. We estimated odds ratios (ORs) and 95% confidence intervals (CIs) using unconditional logistic regression models. All statistical tests were two-sided.A lower risk of CRC was associated with regular aspirin use and the T allele of rs6983267. The effect of aspirin was confined to individuals with protective T allele of rs6983267 (additive matching factorsadjusted OR for T allele 0.83; 95% CI 0.74 to 0.94; P-trend .002; P-interaction .01). Additionally, the T allele of rs6983267 was associated with a reduced expression of MYC oncogene (P-trend .03). Moreover, among individuals with protective T allele, the effect of regular aspirin use was limited to those with positive nuclear CTNNB1 expression. In a functional analysis, in vitro treatment of LS174T cells (a cell line heterozygous for rs6983267) with aspirin was statistically significantly associated with higher G/T allelic ratio of TCF7L2 immunoprecipitated DNA (P .03).Our results support an influence of aspirin on WNT/CTNNB1 signaling and suggest that aspirin chemoprevention may be tailored according to rs6983267 genotype.