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

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Cell cycle checkpoint regulation is crucial for the prevention of carcinogenesis in mammalian cells. To test the hypothesis that common sequence variants in the cell cycle control pathway may affect bladder cancer susceptibility, we evaluated the effect of a comprehensive panel of 11 single nucleotide polymorphisms (SNPs) from seven cell cycle control genes including p53, p21, p27, CDK4, CDK6, CCND1, and STK15, on bladder cancer risk in a case control study of 696 bladder cancer cases and 629 healthy controls. Overall, only individuals with p53 intron 3 variant allele-containing genotypes had a significantly altered bladder cancer risk (odds ratio [OR]=0.72, 95% confidence interval [CI] 0.55-0.94). In stratified analyses, former smokers with at least one variant allele of p53 intron 3 polymorphism and current smokers heterozygous for a SNP in the CDK6 3’ untranslated region (UTR) exhibited significantly reduced risk with ORs of 0.65 (0.44-0.96) and 0.46 (0.22-0.93), respectively. We then applied Classification and Regression Tree (CART) and Multifactor Dimensionality Reduction (MDR) statistical approaches to explore the high order gene-gene and gene-environment interactions. In the CART analysis, smoking status was identified as the most influential factor for bladder cancer susceptibility. The final decision tree recursively partitioned by CART contained four terminal nodes. Compared to the low risk group including never smokers who were rare homozygotes for the CDK4 promoter SNP and common homozygotes for CCDN1 P241P, the medium-low (never smokers with CDK4 promoter variant-containing genotypes), medium-high (ever smokers), and high risk groups (never smokers with CDK4 rare homozygous and CCND1 variant-containing genotypes) exhibited significantly elevated bladder cancer risks with ORs of 2.15 (0.45 - 10.28), 5.86 (1.23 - 27.87), and 7.72 (1.31 - 45.33), respectively. The CART findings were further substantiated by genotype-phenotype correlation analyses. Mutagen-sensitivity assay confirmed these findings that high risk individuals exhibited significantly higher number of bleomycin-induced chromosome breaks (P for trend=0.022). MDR results indicated that the six-factor model including smoking status, CCND1 P241P, p53 intron 3, CDK6 3’UTR, CDK4 promoter, and p53 R72P provided the highest prediction accuracy (62.9%) and the best cross-validation consistency (100/100, permutation P<0.001). The above results suggested that cell cycle genetic polymorphisms may impact bladder cancer predisposition through modulating host genome stability and confirmed the importance of studying gene-gene and gene-environment interactions in the bladder cancer risk assessment. Supported by NCI grants CA 74880 and CA 91846.