Comprehensive analyses of DNA repair pathways, smoking and bladder cancer risk in Los Angeles and Shanghai

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Tobacco smoking is a bladder cancer risk factor and a source of carcinogens that induce DNA damage to urothelial cells. Using data and samples from 988 cases and 1,004 controls enrolled in the Los Angeles County Bladder Cancer Study and the Shanghai Bladder Cancer Study, we investigated associations between bladder cancer risk and 632 tagSNPs that comprehensively capture genetic variation in 28 DNA repair genes from four DNA repair pathways: base excision repair (BER), nucleotide excision repair (NER), non-homologous end-joining (NHEJ) and homologous recombination repair (HHR). Odds ratios (ORs) and 95% confidence intervals (CIs) for each tagSNP were corrected for multiple testing for all SNPs within each gene using pACT and for genes within each pathway and across pathways with Bonferroni. Gene and pathway summary estimates were obtained using ARTP. We observed an association between bladder cancer andPOLBrs7832529 (BER) (pACT = 0.003;ppathway = 0.021) among all, and SNPs inXPC(NER) andOGG1(BER) among Chinese men and women, respectively. The NER pathway showed an overall association with risk among Chinese males (ARTP NERp= 0.034). TheXRCC6SNP rs2284082 (NHEJ), also in LD withSREBF2, showed an interaction with smoking (smoking status interactionpgene = 0.001,ppathway = 0.008,poverall = 0.034). Our findings support a role in bladder carcinogenesis for regions that map close to or within BER (POLB, OGG1) and NER genes (XPC). A SNP that tags both theXRCC6andSREBF2genes strongly modifies the association between bladder cancer risk and smoking.

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DNA repair plays a vital role in maintaining DNA integrity in bladder epithelial cells exposed to carcinogens from tobacco smoke. As a result, genetic variations in DNA repair genes could modify bladder cancer risk. Here, analysis of 28 genes that participate in four DNA repair pathways suggests that certain variants in base excision repair and nucleotide excision repair genes may contribute to bladder cancer formation specifically in Chinese populations. Gene-by-environment interaction analyses that included non-Hispanic whites and Chinese suggest that double strand breaks might be the most detrimental type of tobacco-induced DNA damage leading to bladder cancer.

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