Abstract A1: Comprehensive analyses of DNA repair pathways, smoking, and bladder cancer risk in Los Angeles and Shanghai
Authors: Corral Roman , Xiang Yong-Bing , Yuan Jian-Min , Stern Mariana C. , Lewinger Juan Pablo , Van Den Berg David , Joshi Amit D. , Gago-Dominguez Manuela , Cortessis Victoria K. , Conti David V. , Pike Malcolm , Gao Yu-Tang 
Published: June 2012

Background: Tobacco smoking is a well-established bladder cancer risk factor, and a rich source of chemical carcinogens and reactive oxygen species that can induce a variety of DNA damage to urothelial cells. Selected genetic variants in a few DNA repair genes have been shown to modify both bladder cancer risk and the effect of smoking on this risk. In this study, we conducted genotypic analyses using a set of 571 tagSNPs that comprehensively captured common genetic variation in 27 DNA repair genes corresponding to four DNA repair pathways: base excision repair (BER), nucleotide excision repair (NER), non-homologous end-joining (NHEJ), and homologous recombination repair (HHR).

Methods: We used data and samples from 757 cases and 770 controls enrolled in the Los Angeles County Bladder Cancer Study and 545 cases and 537 controls enrolled in the Shanghai Bladder Cancer Study, for a total of 1,302 cases and 1,307 controls. Genotypic data on all selected tagSNPs was obtained using the Golden Gate Assay (Illumina, Inc). Odds ratios (ORs) and 95% confidence intervals (CIs) for bladder cancer associated with each tagSNP were calculated using conditional logistic regression models and corrected for multiple testing for all SNPs within each gene using pACT, and for different genes within each pathway and across all pathways using the Bonferroni method. The interaction effect between tagSNPs and smoking on bladder cancer risk were tested using conditional logistic regression models and corrected within each gene, pathway and across pathways using the Bonferroni method.

Results: We observed an association between a SNP in the BER pathway (POLB gene; rs7832529; OR = 1.46; 95% CI = 1.17–1.81) that remained statistically significant following correction for all (11) SNPs in POLB (pACT p = 0.006) and further correction for all (7) genes in the BER pathway (p = 0.004), but not after further correction for all pathways considered (4) (p = 0.172). We also observed evidence of gene x years of smoking interactions for a SNP in the NER pathway (XPC gene; rs17038942) that remained statistically significant following correction for all (24) SNPs in XPC (interaction p = 0.003), further correction for all (8) genes within NER (interaction p = 0.003) and further correction for all pathways considered (interaction p = 0.011). Similar findings were observed for pack-years of smoking, where an interaction was also observed for a SNP in the NHEJ (XRCC6 gene, rs4239895)(interaction p for gene = 0.007; interaction p for pathway = 0.044; interaction p for all pathways = 0.178).

Conclusions: Our findings highlight a role in bladder carcinogenesis for genes that play key roles in repair of oxidative damage (POLB, XRCC6 and XPC) and one gene that also plays a role in repair of bulky adducts (XPC).

Citation Information: Cancer Prev Res 2011;4(10 Suppl):A1.