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Comprehensive Analyses of DNA Repair Pathways, Smoking and Bladder Cancer Risk in Los Angeles and Shanghai

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Comprehensive Analyses of DNA Repair Pathways, Smoking and Bladder Cancer Risk in Los Angeles and Shanghai IJC International Journal of Cancer Comprehensive analyses of DNA repair pathways, smoking and bladder cancer risk in Los Angeles and Shanghai Roman Corral1,2, Juan Pablo Lewinger1,2, David Van Den Berg1,2, Amit D. Joshi3, Jian-Min Yuan4, Manuela Gago-Dominguez1,2,5, Victoria K. Cortessis1,2,6, Malcolm C. Pike1,2,7, David V. Conti1,2, Duncan C. Thomas1,2, Christopher K. Edlund2, Yu-Tang Gao8, Yong-Bing Xiang8, Wei Zhang8, Yu-Chen Su1,2 and Mariana C. Stern1,2 1 Department of Preventive Medicine, Keck School of Medicine of USC, University of Southern California, Los Angeles, CA 2 Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA 3 Department of Epidemiology, Harvard School of Public Health, Boston, MA 4 Department of Epidemiology, Graduate School of Public Health, University of Pittsburgh Cancer Institute, University of Pittsbugh, Pittsburgh, PA 5 Galician Foundation of Genomic Medicine, Complexo Hospitalario Universitario Santiago, Servicio Galego de Saude, IDIS, Santiago de Compostela, Spain 6 Department of Obstetrics and Gynecology, Keck School of Medicine of University of Southern California, Los Angeles, CA 7 Department of Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer Center, New York, NY 8 Department of Epidemiology, Shanghai Cancer Institute and Cancer Institute of Shanghai Jiaotong University, Shanghai, China 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 5 0.003; ppathway 5 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 5 0.034). The XRCC6 SNP rs2284082 (NHEJ), also in LD with SREBF2, showed an interaction with smoking (smoking status interaction pgene 5 0.001, ppathway 5 0.008, poverall 5 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. Cancer Genetics Key words: bladder cancer, smoking, DNA repair, POLB, XRCC6 Urinary bladder cancer is among the 10 most common can- Abbreviations: BER: Base excision repair; CI: confidence interval; cers worldwide, with its age standardized incidence rate vary- df: degrees of freedom; DNA: deoxyribonucleic acid; HRR: homol- ing by gender and world regions.1 In Los Angeles County ogous recombination repair; NHW: non-Hispanic White; NOC: non-Hispanic white men have the highest incidence rate of N-nitroso compound; NER: nucleotide excision repair; NHEJ: bladder cancer, followed by Hispanic, African-American and non-homologous end-joining; OR: odds ratio; ROS: reactive oxy- Asian-American men, in spite of comparable profiles of gen species; SNP: single nucleotide polymorphism; tagSNP: haplo- tobacco use. Women show a similar pattern of incidence type tagging SNP rates by race, although the overall rates are much lower than Additional Supporting Information may be found in the online men.2 Chinese from Shanghai have about two-third the inci- version of this article. dence rate of bladder cancer of Chinese in Los Angeles.3 Cig- Grant sponsor: National Cancer Institute; Grant numbers: arette smoking and occupational exposure to arylamines are 1P01CA86871, 1R01CA065726, 1R01CA114665, P30CA014089; the main established risk factors.4 Tobacco smoking contrib- Grant sponsor: NIH; Grant numbers: T32GM067587, 1R01 utes upwards of 50% of bladder cancer occurrence in men ES019876; Grant sponsor: NIEHS; Grant number: 5P30 ES07048; and 20% in women5; although more recent data suggests that Grant sponsor: FIS Intrasalud; Grant number: PS09/02368; Grant in the United States the population attributable risk of smok- sponsor: Botin Foundation ing among men and women might now be comparable.6 In DOI: 10.1002/ijc.28693 addition to smoking and occupational exposure to aryl- 7 History: Received 29 Apr 2013; Accepted 11 Nov 2013; Online 2 amines, use of hair dyes has been identified as a bladder 8 Jan 2014 cancer risk factor. Correspondence to: Dr. Mariana C. Stern, USC/Norris Chemical carcinogens present in tobacco smoke, such Comprehensive Cancer Center, 1441 Eastlake Avenue. Room 5421A. as polycyclic aromatic hydrocarbons, aromatic amines, Los Angeles, CA 90089, USA. Tel.: 323-865-0811, E-mail: heterocyclic amines and N-nitroso compounds and aryl- [email protected] amines from other sources, can induce DNA damage in Int. J. Cancer: 135, 335–347 (2014) VC 2014 UICC 336 DNA repair, smoking and bladder cancer risk What’s new? 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 analy- ses 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. the bladder epithelium.9 In addition, reactive oxygen spe- Material and Methods cies (ROS) present in tobacco smoke,10 and also generated Study population as a by-product of chemical carcinogen metabolism,11,12 Study participants were enrolled as part of two population- can contribute to additional DNA damage. Altogether, based case-control studies of transitional cell carcinoma of the chemical carcinogens and ROS can contribute to the accu- urinary bladder conducted in Los Angeles County, California, mulation of bulky adducts, single (SSB) and double strand USA and Shanghai, China. Characteristics of the Los Angeles breaks (DSB) and various forms of nucleotide base modifi- Bladder Cancer (LABC) and Shanghai Bladder Cancer (SBC) cation or loss which can lead to genomic instability. Modi- studies have been described previously.16,17 Briefly, the Los fiedorlostbasesandSSBsaregenerallyrepairedthrough Angeles County Cancer Surveillance Program was used to the base excision repair pathway (BER). DSBs are repaired identify cases diagnosed with histologically confirmed bladder by either the non-homologous end joining (NHEJ) or the cancer, among non-Asian cases between the ages of 25 and 68 homologous recombination repair (HRR) pathways. Bulky years of age from 1987 through 1996. Using a standard proce- adducts are repaired by the nucleotide excision repair dure,16 controls were identified among residents of the cases’ (NER) pathway. neighborhoods of residence and individually (1:1) matched to Given the important role DNA repair pathways play in cases by gender, race/ethnicity and age (65 years). In Shang- maintaining DNA integrity, it has been postulated that inter- hai, the Shanghai Cancer Registry was used to identify cases individual genetic variation in these pathways may modify diagnosed with histologically confirmed bladder cancer, resi- bladder cancer risk. Consistent with this hypothesis, individu- dents of the city of Shanghai and between the ages of 25 and 74 als with reduced DNA repair proficiency were reported to years of age from 1995 to 1998. A previously described algo- Cancer Genetics have higher risk of developing bladder cancer.13 Several epi- rithm was used to randomly identify population-based controls demiological studies have investigated the bladder cancer from within the city of Shanghai,18 who were frequency associations with candidate polymorphisms in selected DNA matched to bladder cancer cases by gender and five year age repair genes, and a large pooled and meta-analysis of most of groups. In-person questionnaires administered to all study par- these studies offered support for a role of selected DNA ticipants were used to collect demographic, lifestyle and medi- repair variants in bladder carcinogenesis.14 More recently, a cal characteristics up to the reference date, which in Los comprehensive analysis of the NER pathway was conducted Angeles was defined for each case-control pair as two years which offered further support for a role for DNA repair var- before the case’s diagnosis and in Shanghai was defined as two iants in bladder cancer risk.15 years prior to diagnosis for cases and two years prior to inter- In this study, we report findings from an extensive view for controls. Mean time interval between bladder cancer pathway-based examination of 632 haplotype-tagging SNPs diagnosis and interview was 11 months for bladder cancer
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