Genome-wide analysis of SNPs associated with TP53 protein dysregulation in bladder tumors.

B198

TP53 is a central regulator of cellular response to stress and is the most commonly inactivated tumor suppressor gene in human tumors, including bladder tumors. Dysregulation of TP53 protein levels is also an important predictor of prognosis for bladder cancer. To assess whether there is a relationship between genetic polymorphisms in cancer - related genes and susceptibility to TP53 dysregulation, we conducted a preliminary analysis of a panel of over 1400 SNPs in hypothesized cancer - related genes using a subset of cases from a population - based study of bladder cancer in the U.S. We performed TP53 immunohistochemical analysis of over 670 bladder tumors. A trained pathologist recorded the percentage of the tumor that stained for TP53 protein and scored the intensity of that staining. Our analytic strategy for high dimension SNP datasets combined both novel algorithms and traditional statistical approaches to explore the relationship between SNPs and the percent or intensity of TP53 staining of bladder tumors. We began by filtering the dataset using a priori hypotheses, p-for-trend, or the Relief F algorithm. Multifactor dimensionality reduction (MDR), classification and regression trees (CART), and hierarchical interaction graphs were used to predict interactions. We tested main effects and the predicted interactions using logistic regression with adjustment for potential confounders. In our initial analysis, individuals with one or two variant alleles in the TP53 gene had increased intensity and percent of TP53 protein staining (adjusted OR for intensity 1.9 (95%CI 1.2 - 3.0)) compared with those without TP53 positive staining. Further, we observed an association between SNPs in the DNA double-strand break DNA repair gene, XRCC5 and both the percentage of cells staining positively for TP53 and the intensity of the staining (homozygous variant genotype adjusted OR for intensity of staining 2.2 95% CI (1.2-4.1)) of bladder tumors. Likewise, we found statistically significant associations between bladder tumor TP53 staining and homozygous variant SNPs in the caspase recruitment domain family member CARD15 (adjusted OR 2.7 (95%CI 1.4-5.4)) and the interleukin 4 receptor IL4R (adjusted OR 2.4 (95%CI 1.2-4.9)). These results suggest genetic susceptibility factors for TP53 dysregulation in bladder tumors. Further investigation of these genes in relation to bladder carcinogenesis and regulation of the TP53 pathway is warranted. (Supported by ES05947, CA102327, CA121382, ES007373)