Genetic polymorphisms in TP53, nonsteroidal anti-inflammatory drugs and the risk of colorectal cancer: Evidence for gene-environment interaction?

OBJECTIVE: Substantial evidence indicates that nonsteroidal anti-inflammatory drugs protect against colorectal cancer by altering cell cycle progression and/or inducing apoptosis, whereas p53 protein is crucial to maintaining cell-cycle arrest and regulating DNA repair, differentiation, and apoptosis. Genetic variants in TP53 gene might therefore influence colorectal cancer risk and modify the effects of nonsteroidal anti-inflammatory drugs. We assessed the association of TP53 Arg72Pro and p53PIN3 polymorphisms with colorectal cancer risk and their possible interaction with nonsteroidal anti-inflammatory drug use. METHODS: We included 467 cases and 563 controls from a population-based case-control study. Multivariate logistic regression analysis was used to estimate the association between genotypes, environmental exposures and colorectal cancer risk, adjusting for potential confounders. RESULTS: Odds ratios of colorectal cancer were 0.75 (95% confidence interval, 0.57-0.99) for TP53 72Pro carriers compared with those homozygous for the TP53 72Arg allele and 0.78 (95% confidence interval, 0.58-1.05) for p53PIN3 A2 carriers compared with p53PIN3 A1A1. Risks differed by nonsteroidal anti-inflammatory drug use. For both investigated TP53 polymorphisms, we found that the colorectal cancer risk associated with regular nonsteroidal anti-inflammatory drug use was statistically significantly modified by the TP53 genotype (P values for interaction=0.049 and 0.034, respectively), whereby a substantial protective effect of nonsteroidal anti-inflammatory drug use was observed for homozygous carriers of the 72Arg allele and of the PIN3 A1 allele (odds ratio 0.44; 95% confidence interval, 0.30-0.65 and odds ratio, 0.45; 95% confidence interval, 0.31-0.65). The interaction between nonsteroidal anti-inflammatory drugs and TP53 genetic polymorphisms was confirmed by haplotype analysis. CONCLUSIONS: These data suggest that the TP53 genotype may modify the influence of nonsteroidal anti-inflammatory drug use on the risk of colorectal cancer. A direct proof of functional analysis is warranted to confirm these findings.