Genetic variants in cell cycle control pathway confer susceptibility to bladder cancer

BACKGROUND. Cell cycle checkpoint regulation is crucial for the prevention of carcinogenesis in mammalian cells. METHODS. To test the hypothesis that common sequence variants in the cell cycle control pathway may affect bladder cancer susceptibility, the effects of a panel of 10 potential functional single nucleotide polymorphisms (SNPs) from 7 cell cycle control genes, P53, P21, P27, CDK4, CDK6, CCND1, and STK15, were evaluated on bladder cancer risk in a case-control study of 696 bladder cancer cases and 629 healthy controls. RESULTS. Overall, on individual SNP analysis only individuals with the p53 intron 3 16-bp duplication polymorphism variant allele had a significantly reduced bladder cancer risk (odds ratio [OR] = 0.74, 95% confidence interval [CI], 0.56-0.96). This effect was more evident in former smokers and younger subjects. We then applied the Classification and Regression Tree (CART) statistical approach to explore the high-order gene-gene and gene-smoking interactions. In the CART analysis, smoking status was identified as the most influential factor for bladder cancer susceptibility. The final decision tree by CART contained 6 terminal nodes. Compared with the second-lowest risk group the ORs for terminal nodes I and 3 to 6 ranged from 0.46 to 6.30. CONCLUSIONS. These results suggest that cell cycle genetic polymorphisms may affect bladder cancer predisposition through modulation of host genome stability and confirm the importance of studying gene-gene and gene-environment interactions in bladder cancer risk assessment.