Medical Oncology

, Volume 27, Issue 2, pp 159–166 | Cite as

Impact of nucleotide excision repair ERCC2 and base excision repair APEX1 genes polymorphism and its association with recurrence after adjuvant BCG immunotherapy in bladder cancer patients of North India

  • Ruchika Gangawar
  • Dinesh Ahirwar
  • Anil Mandhani
  • Rama Devi MittalEmail author
Original Paper


Background Altered DNA repair capacity due to polymorphisms in DNA repair genes may modify response to Bacillus Calmette–Guerin (BCG) immunotherapy for high risk superficial bladder cancer (SBC).We evaluated the prospective outcome of exicision repair cross complementing group 2 (ERCC2) and apurinic/apyriminidic endonuclease (APEX1) gene in tumor recurrence after BCG immunotherapy in SBC patients. Materials and methods The study included 135 SBC patients, of which BCG immunotherapy was received by 74 patients. Genotyping was performed for ERCC2 Asp312Asn (G > A), Lys751Gln (A > C), and APEX1 Asp148Glu (T > G) polymorphisms by restriction fragment length polymorphism PCR and amplification refractory mutation system (ARMS) methods. Results Multiple Cox regression analysis demonstrated association of variant genotype of ERCC2312AA polymorphism with high risk of recurrence in BCG treated patients (HR = 3.07, P = 0.016, P c  = 0.048). Patients with the ERCC2312AA polymorphic genotypes showed shorter recurrence free survival (log-rank, P = 0.005; AA/GA + AA = 14/44) who received BCG treatment. Overall, risk of recurrence in bladder cancer was observed with smokers and size of tumors (1–3 cm) (HR = 1.86, P = 0.023 and HR = 3.19, P = 0.031, respectively). Smokers were identified to be at elevated risk in BCG treated patients (HR = 2.84, P = 0.005). No association was observed with the (ERCC2 Lys751Gln and APEX1 Asp148Glu) polymorphisms and risk of recurrence. Conclusion Our data suggested variant (AA) of ERCC2 312 AA genotype to be associated with high risk of tumor recurrence and reduced recurrence free survival in superficial bladder cancer patients.


BCG immunotherapy Bladder cancer DNA repair capacity Polymorphism Recurrence free survival 



The study was supported by the grant of Department of Science and Technology, New Delhi Government of India, RG is thankful to Council of Scientific and Industrial Research, New Delhi for JRF and DA is thankful to Department of Biotechnology, Pune for SRF.

Funding agency

Department of Science and Technology, New Delhi Government of India.


  1. 1.
    Meyer JP, Persad R, Gillatt DA. Use of Bacille Calmette–Guérin in superficial bladder cancer. Postgrad Med J. 2002;78:449–54. doi: 10.1136/pmj.78.922.449.CrossRefPubMedGoogle Scholar
  2. 2.
    Pashos CL, Botteman MF, Laskin BL, Redaelli A. Bladder cancer: epidemiology, diagnosis, and management. Cancer Pract. 2002;10:311–22. doi: 10.1046/j.1523-5394.2002.106011.x.CrossRefPubMedGoogle Scholar
  3. 3.
    Merz VW, et al. Analysis of early failures after intravesical instillation therapy with Bacille Calmette–Guerin for carcinoma in situ of the bladder. Br J Urol. 1995;75:180–4. doi: 10.1111/j.1464-410X.1995.tb07307.x.CrossRefPubMedGoogle Scholar
  4. 4.
    Zhou W, et al. Polymorphisms in the DNA repair genes XRCC1 and ERCC2, smoking, and lung cancer risk. Cancer Epidemiol Biomarkers Prev. 2003;12:359–65.PubMedGoogle Scholar
  5. 5.
    Gu J, et al. Nucleotide excision repair gene polymorphisms and recurrence after treatment for superficial bladder cancer. Clin Cancer Res. 2005;11:1408–15. doi: 10.1158/1078-0432.CCR-04-1101.CrossRefPubMedGoogle Scholar
  6. 6.
    Schaeffer L, et al. The ERCC2/DNA repair protein is associated with the class II BTF2/TFIIH transcription factor. EMBO J. 1994;13:2388–92.PubMedGoogle Scholar
  7. 7.
    Coin F, Bergmann E, Tremeau-Bravard A, Egly JM. Mutations in XPB and ERCC2 helicases found in xeroderma pigmentosum patients impair the transcription function of TFIIH. EMBO J. 1999;18:1357–66. doi: 10.1093/emboj/18.5.1357.CrossRefPubMedGoogle Scholar
  8. 8.
    Bennett RA, Wilson DM, Wong D, Demple B. Interaction of human apurinic endonuclease and DNA polymerase beta in the base excision repair pathway. Proc Natl Acad Sci. 1997;94:7166–9. doi: 10.1073/pnas.94.14.7166.CrossRefPubMedGoogle Scholar
  9. 9.
    Lu AL, Li X, Gu Y, Wright PM, Chang DY. Repair of oxidative DNA damage: mechanisms and functions. Cell Biochem Biophys. 2001;35:141–70. doi: 10.1385/CBB:35:2:141.CrossRefPubMedGoogle Scholar
  10. 10.
    Goode EL, Ulrich CM, Potter JD. Polymorphisms in DNA repair genes and associations with cancer risk. Cancer Epidemiol Biomarkers Prev. 2002;11:1513–30.PubMedGoogle Scholar
  11. 11.
    Sobin LH, Wittekind Ch. TNM classification of malignant tumours. 6th ed. New York: Wiley-Liss; 2002. p. 199–202.Google Scholar
  12. 12.
    Miller SA, Dykes DD, Polesky HF. A simple salting out procedure for extracting DNA from human nucleated cells. Nucleic Acids Res. 1998;16:1215. doi: 10.1093/nar/16.3.1215.CrossRefGoogle Scholar
  13. 13.
    Rybicki BA, et al. DNA repair gene XRCC1 and XPD polymorphisms and risk of prostate cancer. Cancer Epidemiol Biomarkers Prev. 2004;1:23–9. doi: 10.1158/1055-9965.EPI-03-0053.CrossRefGoogle Scholar
  14. 14.
    Sanyal S, et al. Polymorphisms in DNA repair and metabolic genes in bladder cancer. Carcinogenesis. 2004;25:729–34. doi: 10.1093/carcin/bgh058.CrossRefPubMedGoogle Scholar
  15. 15.
    Ito H, et al. Gene-environment interactions between the smoking habit and polymorphisms in the DNA repair genes, APE1 Asp148Glu and XRCC1 Arg399Gln, in Japanese lung cancer risk. Carcinogenesis. 2004;25:1395–401. doi: 10.1093/carcin/bgh153.CrossRefPubMedGoogle Scholar
  16. 16.
    Leibovici D, et al. Polymorphisms in inflammation genes and bladder cancer: from initiation to recurrence, progression, and survival. J Clin Oncol. 2005;23:5746–56. doi: 10.1200/JCO.2005.01.598.CrossRefPubMedGoogle Scholar
  17. 17.
    Gangwar R, Manchanda PK, Mittal RD. Implications of XRCC1, XPD and APE1 gene polymorphism in North Indian population: a comparative approach in different ethnic groups worldwide. Genetica. 2008 [Epub ahead of print].Google Scholar
  18. 18.
    Bohle A, Brandau S. Immune mechanisms in Bacillus Calmette–Guerin immunotherapy for superficial bladder cancer. J Urol. 2003;170:964–9. doi: 10.1097/01.ju.0000073852.24341.4a.CrossRefPubMedGoogle Scholar
  19. 19.
    Mitra S, Boldogh I, Izumi T, Hazra TK. Complexities of the DNA base excision repair pathway for repair of oxidative DNA damage. Environ Mol Mutagen. 2001;38:180–90. doi: 10.1002/em.1070.CrossRefPubMedGoogle Scholar
  20. 20.
    Sanyal S, De Verdier PJ, Steineck G, Larsson P, Onelöv E, Hemminki K, et al. Polymorphisms in XPD, XPC and the risk of death in patients with urinary bladder neoplasms. Acta Oncol. 2007;46:31–41. doi: 10.1080/02841860600812693.CrossRefPubMedGoogle Scholar
  21. 21.
    Huang M, Dinney CP, Lin X, Lin J, Grossman HB, Wu X. High-order interactions among genetic variants in DNA BER pathway and smoking in bladder cancer susceptibility. Cancer Epidemiol Biomarkers Prev. 2007;16:84–91. doi: 10.1158/1055-9965.EPI-06-0712.CrossRefPubMedGoogle Scholar
  22. 22.
    Schabath MB, Delclos GL, Grossman HB, Wang Y, Lerner SP, Chamberlain RM, et al. Polymorphisms in XPD exons 10 and 23 and bladder cancer risk. Cancer Epidemiol Biomarkers Prev. 2005;14:878–84. doi: 10.1158/1055-9965.EPI-04-0235.CrossRefPubMedGoogle Scholar
  23. 23.
    Stern MC, Johnson LR, Bell DA, Taylor JA. XPD codon 751 polymorphism, metabolism genes, smoking, and bladder cancer risk. Cancer Epidemiol Biomarkers Prev. 2002;11:1004–11.PubMedGoogle Scholar
  24. 24.
    Andrew AS, Nelson HH, Kelsey KT, Moore JH, Meng AC, Casella DP, et al. Concordance of multiple analytical approaches demonstrates a complex relationship between DNA repair gene SNPs, smoking and bladder cancer susceptibility. Carcinogenesis. 2006;27:1030–7. doi: 10.1093/carcin/bgi284.CrossRefPubMedGoogle Scholar
  25. 25.
    Sakano S, Wada T, Matsumoto H, Sugiyama S, Inoue R, Eguchi S, et al. Single nucleotide polymorphisms in DNA repair genes might be prognostic factors in muscle-invasive bladder cancer patients treated with chemoradiotherapy. Br J Cancer. 2006;9:561–70. doi: 10.1038/sj.bjc.6603290.CrossRefGoogle Scholar
  26. 26.
    Wang F, Chang D, Hu F, Sui H, Han B, Li D, et al. DNA repair gene XPD polymorphisms and cancer risk: a meta-analysis based on 56 case-control studies. Cancer Epidemiol Biomarkers Prev. 2008;17:507–17.CrossRefPubMedGoogle Scholar
  27. 27.
    Spitz MR, Wu X, Wang Y, Wang LE, Shete S, Amos CI, et al. Modulation of nucleotide excision repair capacity by XPD polymorphisms in lung cancer patients. Cancer Res. 2001;61:1354–7.PubMedGoogle Scholar
  28. 28.
    Hou SM, Falt S, Angelini S, Yang K, Nyberg F, Lambert B, et al. The XPD variant alleles are associated with increased aromatic DNA adduct level and lung cancer risk. Carcinogenesis. 2002;23:599–603. doi: 10.1093/carcin/23.4.599.CrossRefPubMedGoogle Scholar
  29. 29.
    Capella G, Pera G, Sala N, Agudo A, Rico F, Giudicce GD, et al. DNA repair polymorphisms and the risk of stomach adenocarcinoma and severe chronic gastritis in the EPIC-EURGAST study. Int J Epidemiol. 2008;37:1316–25. doi: 10.1093/ije/dyn145.CrossRefPubMedGoogle Scholar
  30. 30.
    de las Penas R, Sanchez-Ronco M, Alberola V, Taron M, Camps C, Garcia-Carbonero R, et al. Polymorphisms in DNA repair genes modulate survival in cisplatin/gemcitabine-treated non-small-cell lung cancer patients. Ann Oncol. 2006;17:668–75. doi: 10.1093/annonc/mdj135.CrossRefGoogle Scholar
  31. 31.
    Hansen RD, Sørensen M, Tjønneland A, Overvad K, Wallin H, Raaschou-Nielsen O, et al. XPA A23G, XPC Lys939Gln, XPD Lys751Gln and XPD Asp312Asn polymorphisms, interactions with smoking, alcohol and dietary factors, and risk of colorectal cancer. Mutat Res. 2007;619:68–80. doi: 10.1016/j.mrfmmm.2007.02.002.PubMedGoogle Scholar
  32. 32.
    Saldivar JS, Lu KH, Liang D, Gu J, Huang M, Vlastos AT, et al. Moving toward individualized therapy based on NER polymorphisms that predict platinum sensitivity in ovarian cancer patients. Gynecol Oncol. 2007;107(Suppl 1):S223–9. doi: 10.1016/j.ygyno.2007.07.024.CrossRefPubMedGoogle Scholar

Copyright information

© Humana Press Inc. 2009

Authors and Affiliations

  • Ruchika Gangawar
    • 1
  • Dinesh Ahirwar
    • 1
  • Anil Mandhani
    • 1
  • Rama Devi Mittal
    • 1
    Email author
  1. 1.Department of Urology and Renal TransplantationSanjay Gandhi Post Graduate Institute of Medical SciencesLucknowIndia

Personalised recommendations