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An association between DNA repair gene polymorphisms and survival in patients with resected non-small cell lung cancer

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Abstract

DNA repair genetic polymorphisms have been studied extensively in relation to lung cancer susceptibility, but much less is known about their role in clinical outcome modulation. In this report, we examined effect of the XPA −4G>A, XPD Asp312Asn, Leu751Gln, hHR23B Ala249Val, XPG Asp1104His, XRCC1 Arg399Gln, XRCC2 −4234G>C and XRCC3 Thr241Met polymorphisms on overall survival in 162 patients with resected non-small cell lung cancer (NSCLC). The XRCC3 Met/Met genotype was significantly associated with increased risk of death among all patients and men in uni- and multivariate analyses. The risk was higher for adenocarcinoma patients possessing the XRCC3 Met/Met or XRCC1 Gln/Gln genotypes, although their frequency was small. The XRCC1 399Gln allele was also associated with poor prognosis in stage II–IIIA and among older individuals. Men homozygous for the XPD 312 Asn/Asn had significantly better survival with the risk of death being at borderline significance in uni- and multivariate models. Younger cases and ever smokers smoking less than median pack-years showed significantly increased risk of death associated with the XPA −4A allele. A presence of one or two XRCC2 −4234C alleles had a protective effect in males and ever smokers with lower cumulative smoking dose, although the CC genotype was rarely observed. When number of combined risk alleles was considered, we found that carriers of >4 adverse alleles were at significantly increased risk of death in uni- and multivariate models. Therefore, our results indicate that selected genetic polymorphisms in DNA repair genes may influence overall survival in resected NSCLC.

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References

  1. Wojciechowska U, Didkowska J, Zatoński W (2008) Cancer in Poland in 2006. The M. Skłodowska-Curie Memorial Cancer Center and Institute of Oncology, Warszawa

    Google Scholar 

  2. Mountain CF (1997) Revisions in the International System for Staging Lung Cancer. Chest 111:1710–1717

    Article  PubMed  CAS  Google Scholar 

  3. Jemal A, Siegel R, Xu J, Ward E (2010) Cancer statistics, 2010. CA Cancer J Clin 60:277–300

    Article  PubMed  Google Scholar 

  4. Brundage MD, Davies D, Mackillop WJ (2002) Prognostic factors in non-small cell lung cancer: a decade of progress. Chest 122:1037–1057

    Article  PubMed  Google Scholar 

  5. Hoeijmakers JH (2001) Genome maintenance mechanisms for preventing cancer. Nature 411:366–374

    Article  PubMed  CAS  Google Scholar 

  6. Heinen CD, Schmutte C, Fishel R (2002) DNA repair and tumorigenesis: lessons from hereditary cancer syndromes. Cancer Biol Ther 1:477–485

    PubMed  Google Scholar 

  7. Goode EL, Ulrich CM, Potter JD (2002) Polymorphisms in DNA repair genes and associations with cancer risk. Cancer Epidemiol Biomark Prev 11:1513–1530

    CAS  Google Scholar 

  8. Krupa R, Synowiec E, Pawlowska E, Morawiec Z, Sobczuk A, Zadrozny M, Wozniak K, Blasiak J (2009) Polymorphism of the homologous recombination repair genes RAD51 and XRCC3 in breast cancer. Exp Mol Pathol 87:32–35

    Article  PubMed  CAS  Google Scholar 

  9. Stanczyk M, Sliwinski T, Cuchra M, Zubowska M, Bielecka-Kowalska A, Kowalski M, Szemraj J, Mlynarski W, Majsterek I (2011) The association of polymorphisms in DNA base excision repair genes XRCC1, OGG1 and MUTYH with the risk of childhood acute lymphoblastic leukemia. Mol Biol Rep 38:445–451

    Article  PubMed  CAS  Google Scholar 

  10. Madhusudan S, Middleton MR (2005) The emerging role of DNA repair proteins as predictive, prognostic and therapeutic targets in cancer. Cancer Treat Rev 31:603–617

    Article  PubMed  CAS  Google Scholar 

  11. Gu J, Zhao H, Dinney CP, Zhu Y, Leibovici D, Bermejo CE, Grossman HB, Wu X (2005) Nucleotide excision repair gene polymorphisms and recurrence after treatment for superficial bladder cancer. Clin Cancer Res 11:1408–1415

    Article  PubMed  CAS  Google Scholar 

  12. Feng J, Sun X, Sun N, Qin S, Li F, Cheng H, Chen B, Cao Y, Ma J, Cheng L, Lu Z, Ji J, Zhou Y (2009) XPA A23G polymorphism is associated with the elevated response to platinum-based chemotherapy in advanced non-small cell lung cancer. Acta Biochim Biophys Sin 41:429–435

    Article  PubMed  CAS  Google Scholar 

  13. Wu X, Gu J, Wu TT, Swisher SG, Liao Z, Correa AM, Liu J, Etzel CJ, Amos CI, Huang M, Chiang SS, Milas L, Hittelman WN, Ajani JA (2006) Genetic variations in radiation and chemotherapy drug action pathways predict clinical outcomes in esophageal cancer. J Clin Oncol 24:3789–3798

    Article  PubMed  CAS  Google Scholar 

  14. Moreno V, Gemignani F, Landi S, Gioia-Patricola L, Chabrier A, Blanco I, González S, Guino E, Capellà G, Canzian F (2006) Polymorphisms in genes of nucleotide and base excision repair: risk and prognosis of colorectal cancer. Clin Cancer Res 12:2101–2108

    Article  PubMed  CAS  Google Scholar 

  15. Sanyal S, De Verdier PJ, Steineck G, Larsson P, Onelöv E, Hemminki K, Kumar R (2007) Polymorphisms in XPD, XPC and the risk of death in patients with urinary bladder neoplasms. Acta Oncol 46:31–41

    Article  PubMed  CAS  Google Scholar 

  16. Butkiewicz D, Rusin M, Enewold L, Shields PG, Chorazy M, Harris CC (2001) Genetic polymorphisms in DNA repair genes and risk of lung cancer. Carcinogenesis 22:593–597

    Article  PubMed  CAS  Google Scholar 

  17. Matullo G, Palli D, Peluso M, Guarrera S, Carturan S, Celentano E, Krogh V, Munnia A, Tumino R, Polidoro S, Piazza A, Vineis P (2001) XRCC1, XRCC3, XPD gene polymorphisms, smoking and (32)P-DNA adducts in a sample of healthy subjects. Carcinogenesis 22:1437–1445

    Article  PubMed  CAS  Google Scholar 

  18. Au WW, Salama SA, Sierra-Torres CH (2003) Functional characterization of polymorphisms in DNA repair genes using cytogenetic challenge assays. Environ Health Perspect 111:1843–1850

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  20. Improta G, Sgambato A, Bianchino G, Zupa A, Grieco V, La Torre G, Traficante A, Cittadini A (2008) Polymorphisms of the DNA repair genes XRCC1 and XRCC3 and risk of lung and colorectal cancer: a case-control study in a Southern Italian population. Anticancer Res 28:2941–2946

    PubMed  CAS  Google Scholar 

  21. de las Peñas R, Sanchez-Ronco M, Alberola V, Taron M, Camps C, Garcia-Carbonero R, Massuti B, Queralt C, Botia M, Garcia-Gomez R, Isla D, Cobo M, Santarpia M, Cecere F, Mendez P, Sanchez JJ, Rosell R (2006) Polymorphisms in DNA repair genes modulate survival in cisplatin/gemcitabine-treated non-small-cell lung cancer patients. Ann Oncol 17:668–675

    Article  Google Scholar 

  22. Yin Z, Zhou B, He Q, Li M, Guan P, Li X, Cui Z, Xue X, Su M, Ma R, Bai W, Xia S, Jiang Y, Xu S, Lv Y, Li X (2009) Association between polymorphisms in DNA repair genes and survival of non-smoking female patients with lung adenocarcinoma. BMC Cancer 9:439

    Article  PubMed  Google Scholar 

  23. Lunn RM, Langlois RG, Hsieh LL, Thompson CL, Bell DA (1999) XRCC1 polymorphisms: effects on aflatoxin B1-DNA adducts and glycophorin A variant frequency. Cancer Res 59:2557–2561

    PubMed  CAS  Google Scholar 

  24. Kiyohara C, Takayama K, Nakanishi Y (2006) Association of genetic polymorphisms in the base excision repair pathway with lung cancer risk: a meta-analysis. Lung Cancer 54:267–283

    Article  PubMed  Google Scholar 

  25. Schneider J, Classen V, Helmig S (2008) XRCC1 polymorphism and lung cancer risk. Expert Rev Mol Diagn 8:761–780

    Article  PubMed  CAS  Google Scholar 

  26. Misra RR, Ratnasinghe D, Tangrea JA, Virtamo J, Andersen MR, Barrett M, Taylor PR, Albanes D (2003) Polymorphisms in the DNA repair genes XPD, XRCC1, XRCC3, and APE/ref-1, and the risk of lung cancer among male smokers in Finland. Cancer Lett 191:171–178

    Article  PubMed  CAS  Google Scholar 

  27. Hung RJ, Hall J, Brennan P, Boffetta P (2005) Genetic polymorphisms in the base excision repair pathway and cancer risk: a HuGE review. Am J Epidemiol 162:925–942

    Article  PubMed  Google Scholar 

  28. Gurubhagavatula S, Liu G, Park S, Zhou W, Su L, Wain JC, Lynch TJ, Neuberg DS, Christiani DC (2004) XPD and XRCC1 genetic polymorphisms are prognostic factors in advanced non-small-cell lung cancer patients treated with platinum chemotherapy. J Clin Oncol 22:2594–2601

    Article  PubMed  CAS  Google Scholar 

  29. Sreeja L, Syamala VS, Syamala V, Hariharan S, Raveendran PB, Vijayalekshmi RV, Madhavan J, Ankathil R (2008) Prognostic importance of DNA repair gene polymorphisms of XRCC1 Arg399Gln and XPD Lys751Gln in lung cancer patients from India. J Cancer Res Clin Oncol 134:645–652

    Article  PubMed  CAS  Google Scholar 

  30. Artac M, Bozcuk H, Pehlivan S, Akcan S, Pehlivan M, Sever T, Ozdogan M, Savas B (2010) The value of XPD and XRCC1 genotype polymorphisms to predict clinical outcome in metastatic colorectal carcinoma patients with irinotecan-based regimens. J Cancer Res Clin Oncol 136:803–809

    Article  PubMed  CAS  Google Scholar 

  31. Giachino DF, Ghio P, Regazzoni S, Mandrile G, Novello S, Selvaggi G, Gregori D, DeMarchi M, Scagliotti GV (2007) Prospective assessment of XPD Lys751Gln and XRCC1 Arg399Gln single nucleotide polymorphisms in lung cancer. Clin Cancer Res 13:2876–2881

    Article  PubMed  CAS  Google Scholar 

  32. Quintela-Fandino M, Hitt R, Medina PP, Gamarra S, Manso L, Cortes-Funes H, Sanchez-Cespedes M (2006) DNA-repair gene polymorphisms predict favorable clinical outcome among patients with advanced squamous cell carcinoma of the head and neck treated with cisplatin-based induction chemotherapy. J Clin Oncol 24:4333–4339

    Article  PubMed  CAS  Google Scholar 

  33. Stoehlmacher J, Ghaderi V, Iobal S, Groshen S, Tsao-Wei D, Park D, Lenz HJ (2001) A polymorphism of the XRCC1 gene predicts for response to platinum based treatment in advanced colorectal cancer. Anticancer Res 21:3075–3079

    PubMed  CAS  Google Scholar 

  34. Cheng XD, Lu WG, Ye F, Wan XY, Xie X (2009) The association of XRCC1 gene single nucleotide polymorphisms with response to neoadjuvant chemotherapy in locally advanced cervical carcinoma. J Exp Clin Cancer Res 28:91

    Article  PubMed  Google Scholar 

  35. Kiyohara C, Yoshimasu K (2007) Genetic polymorphisms in the nucleotide excision repair pathway and lung cancer risk: a meta-analysis. Int J Med Sci 4:59–71

    PubMed  CAS  Google Scholar 

  36. Wu X, Zhao H, Wei Q, Amos CI, Zhang K, Guo Z, Qiao Y, Hong WK, Spitz MR (2003) XPA polymorphism associated with reduced lung cancer risk and a modulating effect on nucleotide excision repair capacity. Carcinogenesis 24:505–509

    Article  PubMed  CAS  Google Scholar 

  37. Lin J, Swan GE, Shields PG, Benowitz NL, Gu J, Amos CI, de Andrade M, Spitz MR, Wu X (2007) Mutagen sensitivity and genetic variants in nucleotide excision repair pathway: genotype–phenotype correlation. Cancer Epidemiol Biomark Prev 16:2065–2071

    Article  CAS  Google Scholar 

  38. Butkiewicz D, Krześniak M, Vaitiekunaite R, Sikora B, Bowman ED, Harris CC, Rusin M (2010) A functional analysis of G23A polymorphism and the alternative splicing in the expression of the XPA gene. Cell Mol Biol Lett 15:611–629

    Article  PubMed  CAS  Google Scholar 

  39. Saldivar JS, Lu KH, Liang D, Gu J, Huang M, Vlastos AT, Follen M, Wu X (2007) Moving toward individualized therapy based on NER polymorphisms that predict platinum sensitivity in ovarian cancer patients. Gynecol Oncol 107:S223–S229

    Article  PubMed  Google Scholar 

  40. Spitz MR, Wu X, Wang Y, Wang LE, Shete S, Amos CI, Guo Z, Lei L, Mohrenweiser H, Wei Q (2001) Modulation of nucleotide excision repair capacity by XPD polymorphisms in lung cancer patients. Cancer Res 61:1354–1357

    PubMed  CAS  Google Scholar 

  41. Booton R, Ward T, Heighway J, Taylor P, Power F, Ashcroft L, Morris J, Thatcher N (2006) Xeroderma pigmentosum group D haplotype predicts for response, survival, and toxicity after platinum-based chemotherapy in advanced nonsmall cell lung cancer. Cancer 106:2421–2427

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

We wish to thank Ms. H. Paterak and Mrs. I. Matuszczyk for their excellent technical assistance and Mrs. Z. Kołosza from the Department of Epidemiology and Silesia Cancer Registry, MSC Memorial Cancer Center and Institute of Oncology in Gliwice, for help in collection of survival data. We are grateful to Drs. J. Harasim, K. Czyżewski and J. Gawrychowski and the staff from the Department of Thoracic Surgery, Medical University of Silesia in Zabrze, for help in sample and clinical data collection. This work was supported partly by grants from Polish State Committee for Scientific Research (KBN) no 6 P207 064 05p02 and no 4 P05A 062 17, and grant no MZ/HHS-93133 from Polish-American MSC II Fund.

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  1. Center for Translational Research and Molecular Biology of Cancer, M. Skłodowska-Curie Memorial Cancer Center and Institute of Oncology, Gliwice Branch, Wybrzeże Armii Krajowej 15, 44-101, Gliwice, Poland

    Dorota Butkiewicz, Marek Rusin, Bożena Sikora, Antonina Lach & Mieczysław Chorąży

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  1. Dorota Butkiewicz
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Correspondence to Dorota Butkiewicz.

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Butkiewicz, D., Rusin, M., Sikora, B. et al. An association between DNA repair gene polymorphisms and survival in patients with resected non-small cell lung cancer. Mol Biol Rep 38, 5231–5241 (2011). https://doi.org/10.1007/s11033-010-0674-1

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