DNA repair polymorphisms modify bladder cancer risk: A multi-factor analytic strategy

Objectives: A number of common non-synonymous single nucleotide polymorphisms ( SNPs) in DNA repair genes have been reported to modify bladder cancer risk. These include: APE1-Asn148Gln, XRCC1- Arg399Gln and XRCC1-Arg194Trp in the BER pathway, XPD- Gln751Lys in the NER pathway and XRCC3- Thr241Met in the DSB repair pathway. Methods: To examine the independent and interacting effects of these SNPs in a large study group, we analyzed these genotypes in 1,029 cases and 1,281 controls enrolled in two case- control studies of incident bladder cancer, one conducted in New Hampshire, USA and the other in Turin, Italy. Results: The odds ratio among current smokers with the variant XRCC3-241 ( TT) genotype was 1.7 ( 95% Cl 1.0 - 2.7) compared to wildtype. We evaluated gene- environment and gene- gene interactions using four analytic approaches: logistic regression, Multifactor Dimensionality Reduction ( MDR), hierarchical interaction graphs, classification and regression trees ( CART), and logic regression analyses. All five methods supported a gene- gene interaction between XRCC1- 399/ XRCC3- 241 ( p = 0.001) ( adjusted OR for XRCC1- 399 GG, XRCC3- 241 TT vs. wildtype 2.0 ( 95% Cl 1.4 - 3.0)). Three methods predicted an interaction between XRCC1- 399/ XPD- 751 ( p = 0.008) ( adjusted OR for XRCC1- 399 GA or AA, XRCC3- 241 AA vs. wild- type 1.4 ( 95% Cl 1.1 - 2.0)). Conclusions: These results support the hypothesis that common polymorphisms in DNA repair genes modify bladder cancer risk and highlight the value of using multiple complementary analytic approaches to identify multi- factor interactions. Copyright (C) 2007 S. Karger AG, Basel.