Tumor Biology

, Volume 35, Issue 3, pp 1933–1944 | Cite as

DNA repair gene XRCC3 polymorphisms and bladder cancer risk: a meta-analysis

  • Qiliu Peng
  • Cuiju Mo
  • Weizhong Tang
  • Zhiping Chen
  • Ruolin Li
  • Limin Zhai
  • Shi Yang
  • Junrong Wu
  • Jingzhe Sui
  • Shan Li
  • Xue Qin
Research Article


The X-ray repair cross-complementing group 3 (XRCC3) in homologous recombination repair (HRR) pathway plays a vital role in DNA double-strand break repair (DSBR). Variants in the XRCC3 gene might result in altered protein structure or function which may influence DSBR efficiency and lead to cancer. Numerous epidemiological studies have been conducted to evaluate the association between XRCC3 polymorphisms and bladder cancer risk. However, the results of these previous studies have been inconsistent. To derive a more precise estimation of the association, we performed a meta-analysis of all available studies relating XRCC3 polymorphisms and bladder cancer. All studies published up to April 2013 on the association between XRCC3 polymorphisms and bladder cancer risk were identified by searching electronic databases PubMed, EMBASE, and Chinese Biomedical Literature databases. The association between the XRCC3 polymorphisms and bladder cancer risk was assessed by odds ratios (ORs) together with their 95 % confidence intervals (CIs). A total of 16 case–control studies met the inclusion criteria and were selected. With respect to C18067T polymorphism, significant increased bladder cancer risk was found when all eligible studies were pooled into the meta-analysis (TT vs. CC: OR = 1.174, 95%CI = 1.033–1.335, P = 0.014 and recessive model TT vs. TC + CC: OR = 1.147, 95 %CI = 1.020–1.290, P = 0.022, respectively). The results were still significant after excluding the Hardy–Weinberg equilibrium violation studies (TT vs. CC: OR = 1.178, 95 %CI = 1.036–1.339, P = 0.013 and recessive model TT vs. TC + CC: OR = 1.144, 95 %CI = 1.017–1.287, P = 0.025, respectively). In subgroup analysis by ethnicity, significant elevated risk was found among Asians (dominant model TT + TC vs. CC: OR = 1.285, 95 %CI = 1.012–1.631). In the subgroup analyses according to smoking status, no significant association was detected in all genetic comparison models. With respect to A17893G and A4541G polymorphisms, no significant association with bladder cancer risk was observed in the overall and subgroup analyses. This meta-analysis suggests that the XRCC3 C18067T polymorphism was associated with increased bladder cancer risk especially among Asians. However, the XRCC3 A17893G and A4541G polymorphisms may not play important roles in bladder carcinogenesis. Further studies with larger sample sizes are needed to validate our finds.


Bladder cancer X-ray repair cross-complementing group 3 Polymorphism Meta-analysis 



The work described in this paper was supported by the National Natural Science Foundation (No. 81060199).

Conflicts of interest



  1. 1.
    Sanyal S, Festa F, Sakano S, Zhang Z, Steineck G, Norming U, et al. Polymorphisms in DNA repair and metabolic genes in bladder cancer. Carcinogenesis. 2004;25:729–34.PubMedCrossRefGoogle Scholar
  2. 2.
    Cohen SM, Shirai T, Steineck G. Epidemiology and etiology of premalignant and malignant urothelial changes. Scand J Urol Nephrol Suppl 2000:105–15.Google Scholar
  3. 3.
    Cavalieri E, Frenkel K, Liehr JG, Rogan E, Roy D. Estrogens as endogenous genotoxic agents—DNA adducts and mutations. J Natl Cancer Inst Monogr 2000:75–93.Google Scholar
  4. 4.
    Johnson-Thompson MC, Guthrie J. Ongoing research to identify environmental risk factors in breast carcinoma. Cancer. 2000;88:1224–9.PubMedCrossRefGoogle Scholar
  5. 5.
    Brenneman MA, Weiss AE, Nickoloff JA, Chen DJ. Xrcc3 is required for efficient repair of chromosome breaks by homologous recombination. Mutat Res. 2000;459:89–97.PubMedCrossRefGoogle Scholar
  6. 6.
    Griffin CS. Aneuploidy, centrosome activity and chromosome instability in cells deficient in homologous recombination repair. Mutat Res. 2002;504:149–55.PubMedCrossRefGoogle Scholar
  7. 7.
    Matullo G, Palli D, Peluso M, Guarrera S, Carturan S, Celentano E, et al. XRCC1, XRCC3, XPD gene polymorphisms, smoking and (32)p-DNA adducts in a sample of healthy subjects. Carcinogenesis. 2001;22:1437–45.PubMedCrossRefGoogle Scholar
  8. 8.
    Sun H, Qiao Y, Zhang X, Xu L, Jia X, Sun D, et al. Xrcc3 thr241met polymorphism with lung cancer and bladder cancer: a meta-analysis. Cancer Sci. 2010;101:1777–82.PubMedCrossRefGoogle Scholar
  9. 9.
    Li F, Li C, Jiang Z, Ma N, Gao X. XRCC3 T241M polymorphism and bladder cancer risk: a meta-analysis. Urology. 2011;77:511.e511–515.Google Scholar
  10. 10.
    Stroup DF, Berlin JA, Morton SC, Olkin I, Williamson GD, Rennie D, et al. Meta-analysis of observational studies in epidemiology: a proposal for reporting. Meta-Analysis of Observational Studies in Epidemiology (MOOSE) group. JAMA. 2000;283:2008–12.PubMedCrossRefGoogle Scholar
  11. 11.
    Thakkinstian A, McEvoy M, Minelli C, Gibson P, Hancox B, Duffy D, et al. Systematic review and meta-analysis of the association between {beta}2-adrenoceptor polymorphisms and asthma: a huge review. Am J Epidemiol. 2005;162:201–11.PubMedCrossRefGoogle Scholar
  12. 12.
    DerSimonian R, Laird N. Meta-analysis in clinical trials. Control Clin Trials. 1986;7:177–88.PubMedCrossRefGoogle Scholar
  13. 13.
    Mantel N, Haenszel W. Statistical aspects of the analysis of data from retrospective studies of disease. J Natl Cancer Inst. 1959;22:719–48.PubMedGoogle Scholar
  14. 14.
    Galbraith RF. A note on graphical presentation of estimated odds ratios from several clinical trials. Stat Med. 1988;7:889–94.PubMedCrossRefGoogle Scholar
  15. 15.
    Egger M, Davey Smith G, Schneider M, Minder C. Bias in meta-analysis detected by a simple, graphical test. BMJ. 1997;315:629–34.PubMedCentralPubMedCrossRefGoogle Scholar
  16. 16.
    Gangwar R, Ahirwar D, Mandhani A, Mittal RD. Do DNA repair genes OGG1, XRCC3 and XRCC7 have an impact on susceptibility to bladder cancer in the north Indian population? Mutat Res. 2009;680:56–63.PubMedCrossRefGoogle Scholar
  17. 17.
    Andrew AS, Mason RA, Kelsey KT, Schned AR, Marsit CJ, Nelson HH, et al. DNA repair genotype interacts with arsenic exposure to increase bladder cancer risk. Toxicol Lett. 2009;187:10–4.PubMedCentralPubMedCrossRefGoogle Scholar
  18. 18.
    Matullo G, Guarrera S, Carturan S, Peluso M, Malaveille C, Davico L, et al. DNA repair gene polymorphisms, bulky DNA adducts in white blood cells and bladder cancer in a case–control study. Int J Cancer. 2001;92:562–7.PubMedCrossRefGoogle Scholar
  19. 19.
    Ricceri F, Guarrera S, Sacerdote C, Polidoro S, Allione A, Fontana D, et al. ERCC1 haplotypes modify bladder cancer risk: a case–control study. DNA Repair (Amst). 2010;9:191–200.PubMedCrossRefGoogle Scholar
  20. 20.
    Mittal RD, Gangwar R, Mandal RK, Srivastava P, Ahirwar DK. Gene variants of XRCC4 and XRCC3 and their association with risk for urothelial bladder cancer. Mol Biol Rep. 2012;39:1667–75.PubMedCrossRefGoogle Scholar
  21. 21.
    Zhu X, Zhong Z, Zhang X, Zhao X, Xu R, Ren W, et al. DNA repair gene XRCC3 T241M polymorphism and bladder cancer risk in a Chinese population. Genet Test Mol Biomark. 2012;16:640–3.CrossRefGoogle Scholar
  22. 22.
    Andrew AS, Karagas MR, Nelson HH, Guarrera S, Polidoro S, Gamberini S, et al. DNA repair polymorphisms modify bladder cancer risk: a multi-factor analytic strategy. Hum Hered. 2008;65:105–18.PubMedCrossRefGoogle Scholar
  23. 23.
    Narter KF, Ergen A, Agachan B, Gormus U, Timirci O, Isbir T. Bladder cancer and polymorphisms of DNA repair genes (XRCC1, XRCC3, XPD, XPG, APE1, HOGG1). Anticancer Res. 2009;29:1389–93.PubMedGoogle Scholar
  24. 24.
    Fontana L, Bosviel R, Delort L, Guy L, Chalabi N, Kwiatkowski F, et al. DNA repair gene ERCC2, XPC, XRCC1, XRCC3 polymorphisms and associations with bladder cancer risk in a French cohort. Anticancer Res. 2008;28:1853–6.PubMedGoogle Scholar
  25. 25.
    Figueroa JD, Malats N, Rothman N, Real FX, Silverman D, Kogevinas M, et al. Evaluation of genetic variation in the double-strand break repair pathway and bladder cancer risk. Carcinogenesis. 2007;28:1788–93.PubMedCrossRefGoogle Scholar
  26. 26.
    Matullo G, Dunning AM, Guarrera S, Baynes C, Polidoro S, Garte S, et al. DNA repair polymorphisms and cancer risk in non-smokers in a cohort study. Carcinogenesis. 2006;27:997–1007.PubMedCrossRefGoogle Scholar
  27. 27.
    Matullo G, Guarrera S, Sacerdote C, Polidoro S, Davico L, Gamberini S, et al. Polymorphisms/haplotypes in DNA repair genes and smoking: a bladder cancer case–control study. Cancer Epidemiol Biomarkers Prev. 2005;14:2569–78.PubMedCrossRefGoogle Scholar
  28. 28.
    Broberg K, Bjork J, Paulsson K, Hoglund M, Albin M. Constitutional short telomeres are strong genetic susceptibility markers for bladder cancer. Carcinogenesis. 2005;26:1263–71.PubMedCrossRefGoogle Scholar
  29. 29.
    Wu X, Gu J, Grossman HB, Amos CI, Etzel C, Huang M, et al. Bladder cancer predisposition: a multigenic approach to DNA-repair and cell-cycle-control genes. Am J Hum Genet. 2006;78:464–79.PubMedCentralPubMedCrossRefGoogle Scholar
  30. 30.
    Stern MC, Umbach DM, Lunn RM, Taylor JA. DNA repair gene XRCC3 codon 241 polymorphism, its interaction with smoking and xrcc1 polymorphisms, and bladder cancer risk. Cancer Epidemiol Biomarkers Prev. 2002;11:939–43.PubMedGoogle Scholar
  31. 31.
    Covolo L, Placidi D, Gelatti U, Carta A, Scotto Di Carlo A, Lodetti P, et al. Bladder cancer, GSTS, NAT1, NAT2, SULT1A1, XRCC1, XRCC3, XPD genetic polymorphisms and coffee consumption: a case–control study. Eur J Epidemiol. 2008;23:355–62.PubMedCrossRefGoogle Scholar
  32. 32.
    Shen M, Hung RJ, Brennan P, Malaveille C, Donato F, Placidi D, et al. Polymorphisms of the DNA repair genes XRCC1, XRCC3, XPD, interaction with environmental exposures, and bladder cancer risk in a case–control study in northern Italy. Cancer Epidemiol Biomarkers Prev. 2003;12:1234–40.PubMedGoogle Scholar
  33. 33.
    Yang KX, Chen K, Han QH. DNA repair genes XRCC1 and XRCC3 polymorphisms and bladder cancer risk. Chin J Misdiagn. 2009;9:8383–4.Google Scholar
  34. 34.
    Hao GY, Zhang YY, Zhang WD, Yang MS. Relationship between XRCC3 gene polymorphism and bladder cancer in the Han population. J ShanDong Univ. 2008;46:612–5.Google Scholar
  35. 35.
    Wood RD, Mitchell M, Sgouros J, Lindahl T. Human DNA repair genes. Science. 2001;291:1284–9.PubMedCrossRefGoogle Scholar
  36. 36.
    Hoeijmakers JH. Genome maintenance mechanisms for preventing cancer. Nature. 2001;411:366–74.PubMedCrossRefGoogle Scholar
  37. 37.
    Zhang L, Zhang Z, Yan W. Single nucleotide polymorphisms for DNA repair genes in breast cancer patients. Clin Chim Acta. 2005;359:150–5.PubMedCrossRefGoogle Scholar
  38. 38.
    Garcia-Closas M, Malats N, Real FX, Welch R, Kogevinas M, Chatterjee N, et al. Genetic variation in the nucleotide excision repair pathway and bladder cancer risk. Cancer Epidemiol Biomarkers Prev. 2006;15:536–42.PubMedCrossRefGoogle Scholar
  39. 39.
    Freedman ND, Silverman DT, Hollenbeck AR, Schatzkin A, Abnet CC. Association between smoking and risk of bladder cancer among men and women. JAMA. 2011;306:737–45.PubMedCentralPubMedCrossRefGoogle Scholar
  40. 40.
    Morrison AS, Buring JE, Verhoek WG, Aoki K, Leck I, Ohno Y, et al. An international study of smoking and bladder cancer. J Urol. 1984;131:650–4.PubMedGoogle Scholar
  41. 41.
    Benhamou S, Sarasin A. ERCC2/XPD gene polymorphisms and lung cancer: a huge review. Am J Epidemiol. 2005;161:1–14.PubMedCrossRefGoogle Scholar
  42. 42.
    Friedberg EC. DNA damage and repair. Nature. 2003;421:436–40.PubMedCrossRefGoogle Scholar
  43. 43.
    Manuguerra M, Saletta F, Karagas MR, Berwick M, Veglia F, Vineis P, et al. XRCC3 and XPD/ERCC2 single nucleotide polymorphisms and the risk of cancer: a huge review. Am J Epidemiol. 2006;164:297–302.PubMedCrossRefGoogle Scholar
  44. 44.
    Mitchell AA, Cutler DJ, Chakravarti A. Undetected genotyping errors cause apparent overtransmission of common alleles in the transmission/disequilibrium test. Am J Hum Genet. 2003;72:598–610.PubMedCentralPubMedCrossRefGoogle Scholar
  45. 45.
    Hosking L, Lumsden S, Lewis K, Yeo A, McCarthy L, Bansal A, et al. Detection of genotyping errors by Hardy–Weinberg equilibrium testing. Eur J Hum Genet. 2004;12:395–9.PubMedCrossRefGoogle Scholar
  46. 46.
    Salanti G, Amountza G, Ntzani EE, Ioannidis JP. Hardy–Weinberg equilibrium in genetic association studies: an empirical evaluation of reporting, deviations, and power. Eur J Hum Genet. 2005;13:840–8.PubMedCrossRefGoogle Scholar
  47. 47.
    Trikalinos TA, Salanti G, Khoury MJ, Ioannidis JP. Impact of violations and deviations in Hardy–Weinberg equilibrium on postulated gene–disease associations. Am J Epidemiol. 2006;163:300–9.PubMedCrossRefGoogle Scholar

Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2013

Authors and Affiliations

  • Qiliu Peng
    • 1
  • Cuiju Mo
    • 1
  • Weizhong Tang
    • 2
  • Zhiping Chen
    • 3
  • Ruolin Li
    • 4
  • Limin Zhai
    • 1
  • Shi Yang
    • 1
  • Junrong Wu
    • 1
  • Jingzhe Sui
    • 1
  • Shan Li
    • 1
  • Xue Qin
    • 1
  1. 1.Department of Clinical LaboratoryFirst Affiliated Hospital of Guangxi Medical UniversityNanningChina
  2. 2.Department of Anal and Colorectal SurgeryFirst Affiliated Hospital of Guangxi Medical UniversityNanningChina
  3. 3.Department of Occupational Health and Environmental HealthSchool of Public Health at Guangxi Medical UniversityNanningChina
  4. 4.Department of Medicine ResearchFirst Affiliated Hospital of Guangxi Medical UniversityNanningChina

Personalised recommendations