title: Comprehensive analyses of DNA repair pathways, smoking and bladder cancer risk in Los Angeles and Shanghai.
abstract: 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 and POLB rs7832529 (BER) (pACT = 0.003; ppathway = 0.021) among all, and SNPs in XPC (NER) and OGG1 (BER) among Chinese men and women, respectively. The NER pathway showed an overall association with risk among Chinese males (ARTP NER p = 0.034). The XRCC6 SNP rs2284082 (NHEJ), also in LD with SREBF2, showed an interaction with smoking (smoking status interaction pgene = 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 the XRCC6 and SREBF2 genes strongly modifies the association between bladder cancer risk and smoking.
authors.affiliation: Department of Preventive Medicine, Keck School of Medicine of USC, University of Southern California, Los Angeles, CA; Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA.
authors.forename: Roman
authors.initials: R
authors.lastname: Corral
authors.forename: Juan Pablo
authors.initials: JP
authors.lastname: Lewinger
authors.forename: David
authors.initials: D
authors.lastname: Van Den Berg
authors.forename: Amit D
authors.initials: AD
authors.lastname: Joshi
authors.forename: Jian-Min
authors.initials: JM
authors.lastname: Yuan
authors.forename: Manuela
authors.initials: M
authors.lastname: Gago-Dominguez
authors.forename: Victoria K
authors.initials: VK
authors.lastname: Cortessis
authors.forename: Malcolm C
authors.initials: MC
authors.lastname: Pike
authors.forename: David V
authors.initials: DV
authors.lastname: Conti
authors.forename: Duncan C
authors.initials: DC
authors.lastname: Thomas
authors.forename: Christopher K
authors.initials: CK
authors.lastname: Edlund
authors.forename: Yu-Tang
authors.initials: YT
authors.lastname: Gao
authors.forename: Yong-Bing
authors.initials: YB
authors.lastname: Xiang
authors.forename: Wei
authors.initials: W
authors.lastname: Zhang
authors.forename: Yu-Chen
authors.initials: YC
authors.lastname: Su
authors.forename: Mariana C
authors.initials: MC
authors.lastname: Stern
mesh_terms: D000328:Adult; D000368:Aged; D034961:Antigens, Nuclear / Q000235:genetics*; D002295:Carcinoma, Transitional Cell / Q000235:genetics*; D002681:China; D004260:DNA Repair / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D000072200:Ku Autoantigen; D015141:Los Angeles; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D012307:Risk Factors; D012907:Smoking / Q000009:adverse effects* / Q000235:genetics*; D051782:Sterol Regulatory Element Binding Protein 2 / Q000235:genetics*; D001749:Urinary Bladder Neoplasms / Q000235:genetics*
chemical_list: D034961:Antigens, Nuclear; D004268:DNA-Binding Proteins; C497390:SREBF2 protein, human; D051782:Sterol Regulatory Element Binding Protein 2; C000606509:Xrcc6 protein, human; D000072200:Ku Autoantigen
keywords: DNA repair; POLB; XRCC6; bladder cancer; smoking