Skip to main content

Gene variants of XRCC4 and XRCC3 and their association with risk for urothelial bladder cancer

Molecular Biology Reports volume 39, pages 1667–1675 (2012)Cite this article

Abstract

The DNA double strand break repair gene XRCC4, an important caretaker of genome stability and XRCC3 are suggested to play an imperative role in the development of carcinogenesis. However, no evidence has been provided showing that these genes are associated with risk of urinary bladder cancer (UBC). The study was designed to examine the polymorphisms associated with two genes namely XRCC4 G1394T (rs6869366), intron 3 (rs28360317), intron 7 rs1805377 and rs2836007 and XRCC3 (rs861539 and rs1799796), respectively and investigate their role as susceptible markers for UBC risk in North Indian cohort. In this hospital-based case–control study histologically confirmed 211 UBC patients and 244 age and gender matched controls of similar ethnicity were genotyped by means of PCR-RFLP. Significant different distributions in the frequency of the XRCC4 intron 3 genotype, but not the XRCC4 G1394T or intron 7 genotypes, between the UBC and control groups were observed. XRCC4 intron 7 Del/Del conferred enhanced risk (OR 1.94; P 0.017) in UBC. Interestingly, XRCC −1394 G>T variant genotype GG was associated with reduced risk (OR 0.27; P 0.020). However, none of the four polymorphisms in XRCC4 were associated with tobacco smoking and risk of recurrence in patients treated with BCG immunotherapy. Similarly, none of the XRCC3 polymorphisms were associated with UBC susceptibility. Our results suggested that the XRCC4 intron 3 rs6869366 genotype and intron 7 rs28360317 may be associated with UBC risk and may be a novel useful marker for primary prevention and anticancer intervention.

This is a preview of subscription content, access via your institution.

Access options

Buy single article

Instant access to the full article PDF.

43,34 €

Price includes VAT (Finland)
Tax calculation will be finalised during checkout.

References

  1. Sinha R, Anderson DE, McDonald SS, Greenwald P (2003) Cancer risk and diet in India. J Postgrad Med 49:222–228

    PubMed  CAS  Google Scholar 

  2. Merz VW, Marth D, Kraft R, Ackermann DK, Zingg EJ, Studer UE (1995) Analysis of early failures after intravesical instillation therapy with bacilli Calmette-Guérin for carcinoma in situ of the bladder. Br J Urol 75:180–184

    PubMed  Article  CAS  Google Scholar 

  3. Gao Y, Sun Y, Frank KM, Dikkes P, Fujiwara Y, Seidl KJ et al (1998) A critical role for DNA end-joining proteins in both lymphogenesis and neurogenesis. Cell 95:891–902

    PubMed  Article  CAS  Google Scholar 

  4. Gao Y, Ferguson DO, Xie W, Manis JP, Sekiguchi J, Frank KM et al (2000) Interplay of p53 and DNA-repair protein XRCC4 in tumorigenesis, genomic stability and development. Nature 404:897–900

    PubMed  Article  CAS  Google Scholar 

  5. Griffin CS, Simpson PJ, Wilson CR, Thacker J (2000) Mammalian recombination-repair genes XRCC2 and XRCC3 promote correct chromosome segregation. Nat Cell Biol 2:757–761

    PubMed  Article  CAS  Google Scholar 

  6. Griffin CS (2002) Aneuploidy, centrosome activity and chromosome instability in cells deficient in homologous recombination repair. Mutat Res 504:149–155

    PubMed  Article  CAS  Google Scholar 

  7. Sobin LH, Fleming ID (1997) TNM classification of malignant tumors, fifth edition. Union international contre le cancer and the American joint committee on cancer. Cancer 80:1803–1804

    PubMed  Article  CAS  Google Scholar 

  8. Miller SA, Dykes DD, Polesky HF (1998) A simple salting out procedure for extracting DNA from human nucleated cells. Nucl Acids Res 16:1215

    Article  Google Scholar 

  9. Chiu CF, Tsai MH, Tseng HC, Wang CL, Tsai FJ, Lin CC et al (2008) A novel single nucleotide polymorphism in ERCC6 gene is associated with oral cancer susceptibility in Taiwanese patients. Oral Oncol 44:582–586

    PubMed  Article  CAS  Google Scholar 

  10. López-Cima MF, González-Arriaga P, García-Castro L, Pascual T, Marrón MG, Puente XS et al (2007) Polymorphisms in XPC, XPD, XRCC1, and XRCC3 DNA repair genes and lung cancer risk in a population of northern Spain. BMC Cancer 7:162

    PubMed  Article  Google Scholar 

  11. Werbrouck J, De Ruyck K, Duprez F, Van Eijkeren M, Rietzschel E, Bekaert S et al (2008) Single-nucleotide polymorphisms in DNA double-strand break repair genes: association with head and neck cancer and interaction with tobacco use and alcohol consumption. Mutat Res 656:74–81

    PubMed  CAS  Google Scholar 

  12. Chang CH, Chang CL, Tsai CW, Wu HC, Chiu CF, Wang RF et al (2009) Significant association of an XRCC4 single nucleotide polymorphism with bladder cancer susceptibility in Taiwan. Anticancer Res 29:1777–1782

    PubMed  CAS  Google Scholar 

  13. Broberg K, Björk J, Paulsson K, Höglund M, Albin M (2005) Constitutional short telomeres are strong genetic susceptibility markers for bladder cancer. Carcinogenesis 26:1263–1271

    PubMed  Article  CAS  Google Scholar 

  14. Wu X, Gu J, Grossman HB, Amos CI, Etzel C, Huang M et al (2006) Bladder cancer predisposition: a multigenic approach to DNA-repair and cell-cycle-control genes. Am J Hum Genet 78:464–479

    PubMed  Article  CAS  Google Scholar 

  15. Figueroa JD, Malats N, Rothman N, Real FX, Silverman D, Kogevinas M et al (2007) Evaluation of genetic variation in the double-strand break repair pathway and bladder cancer risk. Carcinogenesis 28:1788–1793

    PubMed  Article  CAS  Google Scholar 

  16. Tseng HC, Tsai MH, Chiu CF, Wang CH, Chang NW, Huang CY et al (2008) Association of XRCC4 codon 247 polymorphism with oral cancer susceptibility in Taiwan. Anticancer Res 28:1687–1691

    PubMed  CAS  Google Scholar 

  17. Chiu CF, Wang HC, Wang CH, Wang CL, Lin CC, Shen CY et al (2008) A new single nucleotide polymorphism in XRCC4 gene is associated with breast cancer susceptibility in Taiwanese patients. Anticancer Res 28:267–270

    PubMed  CAS  Google Scholar 

  18. Chiu CF, Wang CH, Wang CL, Lin CC, Hsu NY, Weng JR et al (2008) A novel single nucleotide polymorphism in XRCC4 gene is associated with gastric cancer susceptibility in Taiwan. Ann Surg Oncol 15:514–518

    PubMed  Article  Google Scholar 

  19. Chiu CF, Tsai MH, Tseng HC, Wang CL, Wang CH, Wu CN et al (2008) A novel single nucleotide polymorphism in XRCC4 gene is associated with oral cancer susceptibility in Taiwanese patients. Oral Oncol 44:898–902

    PubMed  Article  CAS  Google Scholar 

  20. Doré AS, Furnham N, Davies OR, Sibanda BL, Chirgadze DY, Jackson SP et al (2006) Structure of an XRCC4-DNA ligase IV yeast ortholog complex reveals a novel BRCT interaction mode. DNA Repair (Amst) 5:362–368

    Article  Google Scholar 

  21. Fontana L, Bosviel R, Delort L, Guy L, Chalabi N, Kwiatkowski F et al (2008) DNA repair gene ERCC2, XPC, XRCC1, XRCC3 polymorphisms and associations with bladder cancer risk in a French cohort. Anticancer Res 28:1853–1856

    PubMed  CAS  Google Scholar 

  22. Stern MC, Umbach DM, Lunn RM, Taylor JA (2002) DNA repair gene XRCC3 codon 241 polymorphism, its interaction with smoking and XRCC1 polymorphisms, and bladder cancer risk. Cancer Epidemiol Biomarkers Prev 11:939–943

    PubMed  CAS  Google Scholar 

  23. Han S, Zhang HT, Wang Z, Xie Y, Tang R, Mao Y et al (2006) DNA repair gene XRCC3 polymorphisms and cancer risk: a meta-analysis of 48 case-control studies. Eur J Hum Genet 14:1136–1144

    PubMed  Article  CAS  Google Scholar 

  24. Winsey SL, Haldar NA, Marsh HP, Bunce M, Marshall SE, Harris AL et al (2000) A variant within the DNA repair gene XRCC3 is associated with the development of melanoma skin cancer. Cancer Res 60:5612–5616

    PubMed  CAS  Google Scholar 

  25. Matullo G, Guarrera S, Carturan S, Peluso M, Malaveille C, Davico L et al (2001) DNA repair gene polymorphisms, bulky DNA adducts in white blood cells and bladder cancer in a case–control study. Int J Cancer 92:562–567

    PubMed  Article  CAS  Google Scholar 

  26. Jacobsen NR, Raaschou-Nielsen O, Nexø B, Wallin H, Overvad K, Tjønneland A et al (2004) XRCC3 polymorphisms and risk of lung cancer. Cancer Lett 213:67–72

    PubMed  Article  CAS  Google Scholar 

  27. Qiu LX, Mao C, Yao L, Yu KD, Zhan P, Chen B et al (2010) XRCC3 5′-UTR and IVS5–14 polymorphisms and breast cancer susceptibility: a meta-analysis. Breast Cancer Res Treat 122:489–493

    PubMed  Article  CAS  Google Scholar 

  28. Böhle A, Suttmann H, Brandau S (2006) Effect mechanism of intravesical BCG immunotherapy of superficial bladder cancer. Urologe A 45:629–633

    PubMed  Article  Google Scholar 

Download references

Acknowledgments

The authors are grateful to Division of Science and Technology (DST), New Delhi, India for funding. We are thankful to Dr. Mandhani and the senior residents for recruitment of patients and organizing health check-up camps from time to time which was helpful in collecting healthy control blood samples. RG and RKM are thankful to Council of Scientific and Industrial Research (CSIR), New Delhi for Senior Research Fellowship and Junior Research Fellowship.

Conflict of interest

None.

Author information

Affiliations

  1. Department of Urology and Renal Transplantation, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Raebareli Road, Lucknow, 226014, Uttar Pradesh, India

    Rama Devi Mittal, Ruchika Gangwar, Raju K. Mandal, Priyanka Srivastava & Dinesh K. Ahirwar

Authors
  1. Rama Devi Mittal
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ruchika Gangwar
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Raju K. Mandal
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Priyanka Srivastava
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Dinesh K. Ahirwar
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Rama Devi Mittal.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Mittal, R.D., Gangwar, R., Mandal, R.K. et al. Gene variants of XRCC4 and XRCC3 and their association with risk for urothelial bladder cancer. Mol Biol Rep 39, 1667–1675 (2012). https://doi.org/10.1007/s11033-011-0906-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11033-011-0906-z

Keywords

  • Polymorphism
  • Immunotherapy
  • XRCC4
  • XRCC3