Gene-gene interactions in DNA repair pathways impact on prostate cancer risk

Genetic factors may explain approximately 42% of prostate cancer (CaP) risk based on a large-scale twin study. Different DNA repair pathways play critical roles in preserving genome stability; therefore, genetic variations in multiple repair pathways may impact CaP risk. Increasing number of studies show that genetic interactions are more important than single genetic factors for complex diseases. The objective of this study was to detect gene-gene interactions associated with prostate cancer. A total of 890 Caucasians (485 CaP cases and 405 controls) were included in this analysis. We applied Multivariate Adaptive Regression Splines (MARS) and logistic regression (LR) to evaluate 15 non-synonymous single-nucleotide polymorphisms (nsSNPs) in 11 DNA-repair genes of 4 pathways. In the univariate analyses using LR, the ERCC2 312 (NN vs. DD genotype, OR=0.50, 95%CI=0.32-0.77) and MSH3 940 (QQ vs. RR genotype, OR=3.54, 95%CI=1.14-10.96) were significantly associated with CaP risk after adjusting for age, family history, smoking history and benign prostatic hyperplasia. Using MARS, two 3-way gene-gene interactions were found to be significantly associated with CaP risk. Patients with combined ERCC2 312 NN, ADPRT 762 VV and XRCC1 399 RQ/QQ genotypes were significantly associated with lower CaP risk (OR=0.33, 95%CI=0.16-0.68) and the genotype combination of ERCC2 312 DD/DN and XRCC3 241 MM and MSH3 940 RQ/QQ genotypes was significantly associated with higher CaP risk (OR=3.67, 95%CI=1.04-12.94) after adjusting for age, family history, smoking history and benign prostatic hyperplasia. Our results suggest that combined nsSNPs in multiple DNA repair pathways may contribute to CaP risk.