Skip to main content

Advertisement

SpringerLink
Log in

The impact of functional LIG4 polymorphism on platinum-based chemotherapy response and survival in non-small cell lung cancer

  • Original Paper
  • Published:
Medical Oncology Aims and scope Submit manuscript

Abstract

DNA repair capacity is correlated with the sensitivity of cancer cells toward platinum-based chemotherapy. The aim of this study was to investigate whether single-nucleotide polymorphisms (SNPs) in DNA repair genes NBS1, LIG4, and RAD51 were correlated with tumor response in advanced non-small cell lung cancer (NSCLC) patients in a Chinese population who received platinum-based chemotherapy. The treatment outcomes of 146 advanced NSCLC patients who were treated with platinum-based chemotherapy were evaluated. The polymorphic status of three SNPs was determined by genotyping via the polymerase chain reaction–restriction fragment length polymorphism method. Forty-five patients in the group with the CC genotype (45/90) showed a good response to treatment, while only 18 patients in the CT+TT group (18/55) showed a good response, indicating a substantial differences in the chemotherapy response rate based on the LIG4 Thr9Ile polymorphism (P = 0.042). Patients with the GG genotype for the NSB1 Glu185Gln polymorphism were more sensitive to platinum-based chemotherapy compared with patients with either the CG or CC genotype (P = 0.001). Kaplan–Meier analysis of all patients showed a significant association between the LIG4 Thr9Ile CC polymorphism and superior progression-free survival and overall survival (log-rank P = 0.045 and 0.031, respectively). However, there were no significant differences in survival based on the LIG4 Thr9Ile or the RAD51 135G>C polymorphisms. Polymorphisms in the NSB1 and LIG4 genes may be a predictive marker for treatment response and for advanced NSCLC patients in stage IIIB + IV. The CC genotype of the LIG4 Thr9Ile polymorphism may also serve as an independent prognosis factor.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. Yang L, Parkin DM, Li LD, Chen YD, Bray F. Estimation and projection of the national profile of cancer mortality in China: 1991–2005. Br J Cancer. 2004;90(11):2157–66. doi:10.1038/sj.bjc.6601813.

    CAS  PubMed Central  PubMed  Google Scholar 

  2. Bidoli P, Zilembo N, Cortinovis D, Mariani L, Isa L, Aitini E, Cullura D, Pari F, Nova P, Mancin M, Formisano B, Bajetta E. Randomized phase II three-arm trial with three platinum-based doublets in metastatic non-small-cell lung cancer. An Italian Trials in Medical Oncology study. Ann Oncol. 2007;18(3):461–7. doi:10.1093/annonc/mdl415.

    Article  CAS  PubMed  Google Scholar 

  3. Vilmar A, Sorensen JB. Excision repair cross-complementation group 1 (ERCC1) in platinum-based treatment of non-small cell lung cancer with special emphasis on carboplatin: a review of current literature. Lung Cancer. 2009;64(2):131–9. doi:10.1016/j.lungcan.2008.08.006.

    Article  PubMed  Google Scholar 

  4. Bunn PA Jr, Kelly K. New chemotherapeutic agents prolong survival and improve quality of life in non-small cell lung cancer: a review of the literature and future directions. Clin Cancer Res. 1998;4(5):1087–100.

    CAS  PubMed  Google Scholar 

  5. Gurubhagavatula S, Liu G, Park S, Zhou W, Su L, Wain JC, Lynch TJ, Neuberg DS, Christiani DC. XPD and XRCC1 genetic polymorphisms are prognostic factors in advanced non-small-cell lung cancer patients treated with platinum chemotherapy. J Clin Oncol. 2004;22(13):2594–601. doi:10.1200/JCO.2004.08.067.

    Article  CAS  PubMed  Google Scholar 

  6. Zhou W, Gurubhagavatula S, Liu G, Park S, Neuberg DS, Wain JC, Lynch TJ, Su L, Christiani DC. Excision repair cross-complementation group 1 polymorphism predicts overall survival in advanced non-small cell lung cancer patients treated with platinum-based chemotherapy. Clin Cancer Res. 2004;10(15):4939–43. doi:10.1158/1078-0432.CCR-04-0247.

    Article  CAS  PubMed  Google Scholar 

  7. Johnson DH. Gemcitabine for the treatment of non-small-cell lung cancer. Oncology (Williston Park). 2001;15(3 Suppl 6):33–9.

    CAS  Google Scholar 

  8. Jordan P, Carmo-Fonseca M. Molecular mechanisms involved in cisplatin cytotoxicity. Cell Mol Life Sci. 2000;57(8–9):1229–35.

    Article  CAS  PubMed  Google Scholar 

  9. van de Vaart PJ, Belderbos J, de Jong D, Sneeuw KC, Majoor D, Bartelink H, Begg AC. DNA-adduct levels as a predictor of outcome for NSCLC patients receiving daily cisplatin and radiotherapy. Int J Cancer. 2000;89(2):160–6. doi:10.1002/(SICI)1097-0215(20000320)89:2<160:AID-IJC10>3.0.CO;2-J.

    Article  PubMed  Google Scholar 

  10. Lu M, Lu J, Yang X, Yang M, Tan H, Yun B, Shi L. Association between the NBS1 E185Q polymorphism and cancer risk: a meta-analysis. BMC Cancer. 2009;9:124. doi:10.1186/1471-2407-9-124.

    Article  PubMed Central  PubMed  Google Scholar 

  11. Yang T, Chang PY, Park SL, Bastani D, Chang SC, Morgenstern H, Tashkin DP, Mao JT, Papp JC, Rao JY, Cozen W, Mack TM, Greenland S, Zhang ZF. Tobacco smoking, NBS1 polymorphisms, and survival in lung and upper aerodigestive tract cancers with semi-Bayes adjustment for hazard ratio variation. Cancer Causes Control. 2014;25(1):11–23. doi:10.1007/s10552-013-0303-0.

    Article  PubMed  Google Scholar 

  12. Zheng J, Zhang C, Jiang L, You Y, Liu Y, Lu J, Zhou Y. Functional NBS1 polymorphism is associated with occurrence and advanced disease status of nasopharyngeal carcinoma. Mol Carcinog. 2011;50(9):689–96. doi:10.1002/mc.20803.

    Article  CAS  PubMed  Google Scholar 

  13. Yao F, Fang Y, Chen B, Jin F, Wang S. Association between the NBS1 Glu185Gln polymorphism and breast cancer risk: a meta-analysis. Tumour Biol. 2013;34(2):1255–62. doi:10.1007/s13277-013-0668-4.

    Article  CAS  PubMed  Google Scholar 

  14. Yu KD, Yang C, Fan L, Chen AX, Shao ZM. RAD51 135G>C does not modify breast cancer risk in non-BRCA1/2 mutation carriers: evidence from a meta-analysis of 12 studies. Breast Cancer Res Treat. 2011;126(2):365–71. doi:10.1007/s10549-010-0937-5.

    Article  CAS  PubMed  Google Scholar 

  15. Smolarz B, Samulak D, Michalska M, Goralczyk B, Szyllo K, Lewy J, Sporny S, Kokolaszwili G, Burzynski M, Romanowicz-Makowska H. 135G>C and 172G>T polymorphism in the 5’ untranslated region of RAD51 and sporadic endometrial cancer risk in Polish women. Pol J Pathol. 2011;62(3):157–62.

    PubMed  Google Scholar 

  16. Antoniou AC, Sinilnikova OM, Simard J, Leone M, Dumont M, Neuhausen SL, Struewing JP, Stoppa-Lyonnet D, Barjhoux L, Hughes DJ, Coupier I, Belotti M, Lasset C, Bonadona V, Bignon YJ, Rebbeck TR, Wagner T, Lynch HT, Domchek SM, Nathanson KL, Garber JE, Weitzel J, Narod SA, Tomlinson G, Olopade OI, Godwin A, Isaacs C, Jakubowska A, Lubinski J, Gronwald J, Gorski B, Byrski T, Huzarski T, Peock S, Cook M, Baynes C, Murray A, Rogers M, Daly PA, Dorkins H, Schmutzler RK, Versmold B, Engel C, Meindl A, Arnold N, Niederacher D, Deissler H, Spurdle AB, Chen X, Waddell N, Cloonan N, Kirchhoff T, Offit K, Friedman E, Kaufmann B, Laitman Y, Galore G, Rennert G, Lejbkowicz F, Raskin L, Andrulis IL, Ilyushik E, Ozcelik H, Devilee P, Vreeswijk MP, Greene MH, Prindiville SA, Osorio A, Benitez J, Zikan M, Szabo CI, Kilpivaara O, Nevanlinna H, Hamann U, Durocher F, Arason A, Couch FJ, Easton DF, Chenevix-Trench G. RAD51 135G–>C modifies breast cancer risk among BRCA2 mutation carriers: results from a combined analysis of 19 studies. Am J Hum Genet. 2007;81(6):1186–200. doi:10.1086/522611.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  17. Sakiyama T, Kohno T, Mimaki S, Ohta T, Yanagitani N, Sobue T, Kunitoh H, Saito R, Shimizu K, Hirama C, Kimura J, Maeno G, Hirose H, Eguchi T, Saito D, Ohki M, Yokota J. Association of amino acid substitution polymorphisms in DNA repair genes TP53, POLI, REV1 and LIG4 with lung cancer risk. Int J Cancer. 2005;114(5):730–7. doi:10.1002/ijc.20790.

    Article  CAS  PubMed  Google Scholar 

  18. Therasse P, Arbuck SG, Eisenhauer EA, Wanders J, Kaplan RS, Rubinstein L, Verweij J, Van Glabbeke M, van Oosterom AT, Christian MC, Gwyther SG. New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst. 2000;92(3):205–16.

    Article  CAS  PubMed  Google Scholar 

  19. Figueroa JD, Malats N, Rothman N, Real FX, Silverman D, Kogevinas M, Chanock S, Yeager M, Welch R, Dosemeci M, Tardon A, Serra C, Carrato A, Garcia-Closas R, Castano-Vinyals G, Garcia-Closas M. Evaluation of genetic variation in the double-strand break repair pathway and bladder cancer risk. Carcinogenesis. 2007;28(8):1788–93. doi:10.1093/carcin/bgm132.

    Article  CAS  PubMed  Google Scholar 

  20. Yin M, Liao Z, Liu Z, Wang LE, O’Reilly M, Gomez D, Li M, Komaki R, Wei Q. Genetic variants of the nonhomologous end joining gene LIG4 and severe radiation pneumonitis in non-small cell lung cancer patients treated with definitive radiotherapy. Cancer. 2012;118(2):528–35. doi:10.1002/cncr.26214.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  21. Mucha B, Przybylowska-Sygut K, Dziki L, Dziki A, Sygut A, Majsterek I. Lack of association between the 135G/C RAD51 gene polymorphism and the risk of colorectal cancer among Polish population. Pol Przegl Chir. 2012;84(7):358–62. doi:10.2478/v10035-012-0060-x.

    PubMed  Google Scholar 

  22. Chen X, Sun H, Ren S, Kim Curran V, Zhang L, Zhou S, Zhang J, Zhou C. Association of XRCC3 and XPD751 SNP with efficacy of platinum-based chemotherapy in advanced NSCLC patients. Clin Transl Oncol. 2012;14(3):207–13.

    Article  CAS  PubMed  Google Scholar 

  23. Cheng H, Sun N, Sun X, Chen B, Li F, Feng J, Cheng L, Cao Y. Polymorphisms in hMSH2 and hMLH1 and response to platinum-based chemotherapy in advanced non-small-cell lung cancer patients. Acta Biochim Biophys Sin (Shanghai). 2010;42(5):311–7.

    Article  CAS  Google Scholar 

  24. Hu L, Wu C, Zhao X, Heist R, Su L, Zhao Y, Han B, Cao S, Chu M, Dai J, Dong J, Shu Y, Xu L, Chen Y, Wang Y, Lu F, Jiang Y, Yu D, Chen H, Tan W, Ma H, Chen J, Jin G, Wu T, Lu D, Christiani DC, Lin D, Hu Z, Shen H. Genome-wide association study of prognosis in advanced non-small cell lung cancer patients receiving platinum-based chemotherapy. Clin Cancer Res. 2012;18(19):5507–14. doi:10.1158/1078-0432.CCR-12-1202.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  25. Huang RS, Johnatty SE, Gamazon ER, Im HK, Ziliak D, Duan S, Zhang W, Kistner EO, Chen P, Beesley J, Mi S, O’Donnell PH, Fraiman YS, Das S, Cox NJ, Lu Y, Macgregor S, Goode EL, Vierkant RA, Fridley BL, Hogdall E, Kjaer SK, Jensen A, Moysich KB, Grasela M, Odunsi K, Brown R, Paul J, Lambrechts D, Despierre E, Vergote I, Gross J, Karlan BY, Defazio A, Chenevix-Trench G, Dolan ME. Platinum sensitivity-related germline polymorphism discovered via a cell-based approach and analysis of its association with outcome in ovarian cancer patients. Clin Cancer Res. 2011;17(16):5490–500. doi:10.1158/1078-0432.CCR-11-0724.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  26. Tauchi H. Positional cloning and functional analysis of the gene responsible for Nijmegen breakage syndrome, NBS1. J Radiat Res. 2000;41(1):9–17.

    Article  CAS  PubMed  Google Scholar 

  27. Schiller JH, Harrington D, Belani CP, Langer C, Sandler A, Krook J, Zhu J, Johnson DH. Comparison of four chemotherapy regimens for advanced non-small-cell lung cancer. N Engl J Med. 2002;346(2):92–8. doi:10.1056/NEJMoa011954.

    Article  CAS  PubMed  Google Scholar 

  28. Kelly K, Crowley J, Bunn PA Jr, Presant CA, Grevstad PK, Moinpour CM, Ramsey SD, Wozniak AJ, Weiss GR, Moore DF, Israel VK, Livingston RB, Gandara DR. Randomized phase III trial of paclitaxel plus carboplatin versus vinorelbine plus cisplatin in the treatment of patients with advanced non-small-cell lung cancer: a Southwest Oncology Group trial. J Clin Oncol. 2001;19(13):3210–8.

    CAS  PubMed  Google Scholar 

Download references

Acknowledgments

This work was supported by the Provincial Ministry Foundation (Grant No. WKJ2011-2-015), the Province of Important Technology and Science (No. 2011C13039-1), and the National Natural Science Foundation of China (Grant No. 81172081).

Conflict of interest

This study contains no actual or potential conflicts of interest.

Author information

Authors and Affiliations

  1. Department of Thoracic Surgery, Zhejiang Cancer Hospital, Hangzhou, 310022, Zhejiang, China

    You-Hua Jiang, Jian-Guo Feng & Wei-Min Mao

  2. Key Laboratory on Diagnosis and Treatment Technology on Thoracic Cancer, Zhejiang Cancer Hospital (Zhejiang Cancer Research Institute), Hangzhou, 310022, Zhejiang, China

    Xiao-Ling Xu, Wei-Zhen Xu, Dan Li, Qian-Bo Han & Wei-Min Mao

  3. Department of Medical Oncology, Zhejiang Cancer Hospital, 38 Guangji Road, Hangzhou, China

    Xiao-Ling Xu

  4. The Library of Zhejiang University of Media and Communications, Hangzhou, 310022, Zhejiang, China

    Hai-Hong Ruan

Authors
  1. You-Hua Jiang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Xiao-Ling Xu
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Hai-Hong Ruan
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Wei-Zhen Xu
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Dan Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Jian-Guo Feng
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Qian-Bo Han
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Wei-Min Mao
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Wei-Min Mao.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Jiang, YH., Xu, XL., Ruan, HH. et al. The impact of functional LIG4 polymorphism on platinum-based chemotherapy response and survival in non-small cell lung cancer. Med Oncol 31, 959 (2014). https://doi.org/10.1007/s12032-014-0959-7

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1007/s12032-014-0959-7

Keywords

Search

Navigation