It has been posited that aspirin treatment may reduce risk for colorectal cancer through inhibition of WNT/cadherin-associated protein β1 (CTNNB1, or β-catenin) signaling. In a study reported recently in the Journal of the National Cancer Institute, Nan et al investigated the potential role of the single nucleotide polymorphism rs6983267 (chromosome 8q24) in the protective effect of aspirin.1 This colorectal cancer susceptibility locus affects binding activity of transcription factor 7 like-2 (TCF7L2) to CTNNB1 and alters expression of target oncogenes, including MYC. The study showed that the T allele of rs6983267 was associated with a protective effect in regular aspirin users and was associated with reduced MYC expression.
The study involved investigation of regular aspirin use and colorectal cancer risk according to genotypes of rs6983267 and CTNNB1 expression in two prospective case-control studies within the Nurses’ Health Study (women) and the Health Professionals Follow-up Study (men). In total, 840 patients with colorectal cancer and 1,686 age- and race-matched control subjects were included.
On multivariate analysis, a lower risk of colorectal cancer was observed among men (adjusted odds ratio [OR] = 0.80, P = .03), women (OR = 0.85, P = .05), and all patients (OR = 0.83, P = .004) with the T allele. Among subjects of any genotype, regular aspirin use was associated with a significantly reduced risk of colorectal cancer on multivariate analysis (OR = 0.71, P = .0001 for trend).
Effects of T Allele
On multivariate analysis, the protective effect of aspirin was confined to individuals with at least one T allele (P = .01 for interaction). Compared with nonregular use, regular aspirin use was associated with odds ratios for colorectal cancer of 0.61 (P = .0001) among those with GT genotype, 0.52 (P = .002) among those with TT genotype, and 0.99 (P = .94) among those with GG genotype.
On multivariate analysis stratified by rs6983267 genotype, regular aspirin use was associated with significantly lower risk of having colorectal cancer positive for nuclear CTNNB1 expression among patients with the GT or TT genotype (OR = 0.44, P = .003; P = .04 for interaction) but not among those with GG genotype (OR = 0.95, P = .88). In contrast, regular aspirin use was not associated with risk of having tumors negative for nuclear CTNNB1 among either patients with GG genotype (OR = 1.28, P = .49) or those with GT or TT genotype (OR = 0.86, P = .49; P = .33 for interaction).
The investigators concluded, “Our results support an influence of aspirin on WNT/CTNNB1 signaling and suggest that aspirin chemoprevention may be tailored according to rs6983267 genotype.” ■
Disclosure: The study was supported by grants from the National Institutes of Health.