Tan Xiang-Lin, Nieters Alexandra, Hoffmeister Michael, Beckmann Lars, Brenner Hermann, Chang-Claude Jenny
Division of Cancer Epidemiology, German Cancer Research Center, Heidelberg, Germany.
Pharmacogenet Genomics. 2007 Aug;17(8):639-45. doi: 10.1097/FPC.0b013e3280d5121c.
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.
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.
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.
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.
大量证据表明，非甾体抗炎药通过改变细胞周期进程和/或诱导细胞凋亡来预防结直肠癌，而p53蛋白对于维持细胞周期停滞以及调节DNA修复、分化和细胞凋亡至关重要。因此，TP53基因的遗传变异可能会影响结直肠癌风险，并改变非甾体抗炎药的作用效果。我们评估了TP53基因Arg72Pro和p53PIN3多态性与结直肠癌风险的关联，以及它们与使用非甾体抗炎药之间可能存在的相互作用。
我们纳入了一项基于人群的病例对照研究中的467例病例和563例对照。采用多因素逻辑回归分析来估计基因型、环境暴露因素与结直肠癌风险之间的关联，并对潜在的混杂因素进行校正。
与TP53 72Arg等位基因纯合子相比，TP53 72Pro携带者患结直肠癌的比值比为0.75（95%置信区间为0.57 - 0.99）；与p53PIN3 A1A1相比，p53PIN3 A2携带者患结直肠癌的比值比为0.78（95%置信区间为0.58 - 1.05）。风险因使用非甾体抗炎药而有所不同。对于所研究的两种TP53多态性，我们发现TP53基因型在统计学上显著改变了与定期使用非甾体抗炎药相关的结直肠癌风险（交互作用的P值分别为0.049和0.034），由此观察到72Arg等位基因纯合子和PIN3 A1等位基因纯合子使用非甾体抗炎药具有显著的保护作用（比值比分别为0.44；95%置信区间为0.30 - 0.65和比值比为0.45；95%置信区间为0.31 - 0.65）。单倍型分析证实了非甾体抗炎药与TP53基因多态性之间的相互作用。
这些数据表明，TP53基因型可能会改变使用非甾体抗炎药对结直肠癌风险的影响。需要进行功能分析的直接证据来证实这些发现。
