Protective Effect of Aspirin for Colorectal Cancer Is Associated With rs6983267 T Allele
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 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. 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.
Study Details
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.
In total, 135 colorectal cancer cases and 255 controls in the Nurses’ Health study had the rs6983267 GG genotype, 228 and 472 had the GT genotype, and 91 and 250 had the TT genotype. In the Health Professionals Follow-up Study, 103 cases and 150 controls had the GT genotype, 177 and 338 had the GT genotype, and 73 and 158 had the TT genotype.
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).
Reduced MYC Expression
Investigation of the association between rs6983267 genotypes and MYC expression in 189 case patients showed that compared with GG genotype, multivariate odds ratios for MYC overexpression were 0.72 (95% confidence interval [CI] = 0.31–1.68) for GT genotype and 0.32 (95% CI = 0.11–0.89) for TT genotype (P = .03 for trend).
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.”
Andrew T. Chan, MD, MPH, Massachusetts General Hospital, is the corresponding author for the Journal of the National Cancer Institute article.
The study was supported by grants from the National Institutes of Health.
The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.
