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Common variations in ERCC2 are associated with response to cisplatin chemotherapy and clinical outcome in osteosarcoma patients

The Pharmacogenomics Journal volume 9, pages 347–353 (2009)Cite this article

Abstract

Platinum agents cause DNA cross-linking. Nucleotide excision repair genes play a key role in DNA damage repair. This study aims to investigate whether polymorphisms in these genes are associated with tumor response and survival in cisplatin-treated osteosarcoma patients. Eight single nucleotide polymorphisms in ERCC2, XPC, XPA, ERCC1, ERCC4 and ERCC5 genes were analyzed in 91 patients diagnosed with osteosarcoma and treated with cisplatin. A significant association with tumor response, after correction for multiple testing, was found for the Lys751Gln polymorphism in the ERCC2 gene. We found that only 45% of patients with at least one polymorphic G allele responded compared with 80% of patients homozygous for the common T allele (odds ratio=4.9, 95% confidence interval=1.64–14.54, adjusted P-value=0.047). In addition, carrying at least one ERCC2 Lys751GlnG allele was significantly associated with shorter event-free survival (median=184 months, compared with 240 months for TT homozygotes; hazard ratio=5.76, 95% confidence interval=1.30–25.55; P-value=0.021). Although ototoxicity was only recorded in 32 patients, we found weak evidence of an association with the CC genotype of XPC Lys939Gln (P-value= 0.042). This is the first pharmacogenetic study focused on osteosarcoma treatment providing evidence that polymorphic variants in DNA repair genes could be useful predictors of response to cisplatin chemotherapy in osteosarcoma patients.

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References

  1. Marina N, Gebhardt M, Teot L, Gorlick R . Biology and therapeutic advances for pediatric osteosarcoma. Oncologist 2004; 9: 422–441.

    Article  Google Scholar 

  2. Longhi A, Errani C, De Paolis M, Mercuri M, Bacci G . Primary bone osteosarcoma in the pediatric age: state of the art. Cancer Treat Rev 2006; 32: 423–436.

    Article  PubMed  Google Scholar 

  3. Glasser DB, Lane JM, Huvos AG, Marcove RC, Rosen G . Survival, prognosis, and therapeutic response in osteogenic sarcoma. The Memorial Hospital experience. Cancer 1992; 69: 698–708.

    Article  CAS  Google Scholar 

  4. Bielack SS, Kempf-Bielack B, Delling G, Exner GU, Flege S, Helmke K et al. Prognostic factors in high-grade osteosarcoma of the extremities or trunk: an analysis of 1702 patients treated on neoadjuvant cooperative osteosarcoma study group protocols. J Clin Oncol 2002; 20: 776–790.

    Article  PubMed  Google Scholar 

  5. Chou AJ, Gorlick R . Chemotherapy resistance in osteosarcoma: current challenges and future directions. Expert Rev Anticancer Ther 2006; 6: 1075–1085.

    Article  CAS  PubMed  Google Scholar 

  6. Rabik CA, Dolan ME . Molecular mechanisms of resistance and toxicity associated with platinating agents. Cancer Treat Rev 2007; 33: 9–23.

    Article  CAS  Google Scholar 

  7. Zamble DB, Mu D, Reardon JT, Sancar A, Lippard SJ . Repair of cisplatin—DNA adducts by the mammalian excision nuclease. Biochemistry 1996; 35: 10004–10013.

    Article  CAS  PubMed  Google Scholar 

  8. Dabholkar M, Thornton K, Vionnet J, Bostick-Bruton F, Yu JJ, Reed E . Increased mRNA levels of xeroderma pigmentosum complementation group B (XPB) and Cockayne's syndrome complementation group B (CSB) without increased mRNA levels of multidrug-resistance gene (MDR1) or metallothionein-II (MT-II) in platinum-resistant human ovarian cancer tissues. Biochem Pharmacol 2000; 60: 1611–1619.

    Article  CAS  PubMed  Google Scholar 

  9. Quintela-Fandino M, Hitt R, Medina PP, Gamarra S, Manso L, Cortes-Funes H et al. 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 2006; 24: 4333–4339.

    Article  CAS  PubMed  Google Scholar 

  10. Park DJ, Stoehlmacher J, Zhang W, Tsao-Wei DD, Groshen S, Lenz HJ et al. A Xeroderma pigmentosum group D gene polymorphism predicts clinical outcome to platinum-based chemotherapy in patients with advanced colorectal cancer. Cancer Res 2001; 61: 8654–8658.

    CAS  PubMed  Google Scholar 

  11. Gurubhagavatula S, Liu G, Park S, Zhou W, Su L, Wain JC et al. 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: 2594–2601.

    Article  CAS  PubMed  Google Scholar 

  12. Ruzzo A, Graziano F, Loupakis F, Santini D, Catalano V, Bisonni R et al. Pharmacogenetic profiling in patients with advanced colorectal cancer treated with first-line FOLFIRI chemotherapy. Pharmacogenomics J 2008; 8 (4): 278–288.

    Article  CAS  PubMed  Google Scholar 

  13. Clark JC, Dass CR, Choong PF . A review of clinical molecular prognostic factors in osteosarcoma. J Cancer Res Clin Oncol 2007.

  14. Clark JC, Dass CR, Choong PF . A review of clinical and molecular prognostic factors in osteosarcoma. J Cancer Res Clin Oncol 2008; 134: 281–297.

    Article  CAS  PubMed  Google Scholar 

  15. Stoehlmacher J, Park DJ, Zhang W, Yang D, Groshen S, Zahedy S et al. A multivariate analysis of genomic polymorphisms: prediction of clinical outcome to 5-FU/oxaliplatin combination chemotherapy in refractory colorectal cancer. Br J Cancer 2004; 91: 344–354.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Giachino DF, Ghio P, Regazzoni S, Mandrile G, Novello S, Selvaggi G et al. Prospective assessment of XPD Lys751Gln and XRCC1 Arg399Gln single nucleotide polymorphisms in lung cancer. Clin Cancer Res 2007; 13: 2876–2881.

    Article  CAS  PubMed  Google Scholar 

  17. Isla D, Sarries C, Rosell R, Alonso G, Domine M, Taron M et al. Single nucleotide polymorphisms and outcome in docetaxel-cisplatin-treated advanced non-small-cell lung cancer. Ann Oncol 2004; 15: 1194–1203.

    Article  CAS  PubMed  Google Scholar 

  18. Ryu JS, Hong YC, Han HS, Lee JE, Kim S, Park YM et al. Association between polymorphisms of ERCC1 and XPD and survival in non-small-cell lung cancer patients treated with cisplatin combination chemotherapy. Lung Cancer 2004; 44: 311–316.

    Article  PubMed  Google Scholar 

  19. Lunn RM, Helzlsouer KJ, Parshad R, Umbach DM, Harris EL, Sanford KK et al. XPD polymorphisms: effects on DNA repair proficiency. Carcinogenesis 2000; 21: 551–555.

    Article  CAS  Google Scholar 

  20. 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: 1354–1357.

    CAS  PubMed  Google Scholar 

  21. Duell EJ, Wiencke JK, Cheng TJ, Varkonyi A, Zuo ZF, Ashok TD et al. Polymorphisms in the DNA repair genes XRCC1 and ERCC2 and biomarkers of DNA damage in human blood mononuclear cells. Carcinogenesis 2000; 21: 965–971.

    Article  CAS  PubMed  Google Scholar 

  22. Clarkson SG, Wood RD . Polymorphisms in the human XPD (ERCC2) gene, DNA repair capacity and cancer susceptibility: an appraisal. DNA Repair (Amst) 2005; 4: 1068–1074.

    Article  CAS  Google Scholar 

  23. Hu Z, Wang Y, Wang X, Liang G, Miao X, Xu Y et al. DNA repair gene XPC genotypes/haplotypes and risk of lung cancer in a Chinese population. Int J Cancer 2005; 115: 478–483.

    Article  CAS  PubMed  Google Scholar 

  24. Vogel U, Overvad K, Wallin H, Tjønneland A, Nexø BA, Raaschou-Nielsen O et al. Combinations of polymorphisms in XPD XPC and XPA in relation to risk of lung cancer. Cancer Lett 2005; 222: 67–74.

    Article  CAS  PubMed  Google Scholar 

  25. Oldenburg J, Kraggerud SM, Brydøy M, Cvancarova M, Lothe RA, Fossa SD et al. Association between long-term neuro-toxicities in testicular cancer survivors and polymorphisms in lutathione-s-transferase-P1 and -M1, a retrospective cross sectional study. J Transl Med 2007; 5: 70.

    Article  PubMed  PubMed Central  Google Scholar 

  26. Khan SG, Metter EJ, Tarone RE, Bohr VA, Grossman L, Hedayati M et al. A new xeroderma pigmentosum group C poly (AT) insertion/deletion polymorphism. Carcinogenesis 2000; 21: 1821–1825.

    Article  CAS  PubMed  Google Scholar 

  27. Zhu Y, Yang H, Chen Q, Lin J, Grossman HB, Dinney CP et al. Modulation of DNA damage/DNA repair capacity by XPC polymorphisms. DNA Repair (Amst) 2008; 7 (2): 141–148.

    Article  CAS  Google Scholar 

  28. Zhou W, Gurubhagavatula S, Liu G, Park S, Neuberg DS, Wain JC et al. 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: 4939–4943.

    Article  CAS  PubMed  Google Scholar 

  29. Viguier J, Boige V, Miquel C, Pocard M, Giraudeau B, Sabourin JC et al. ERCC1 2004, codon 118 polymorphism is a predictive factor for the tumor response to oxaliplatin/5-fluorouracil combination chemotherapy in patients with advanced colorectal cancer. Clin Cancer Res 2005; 11: 6212–6217.

    Article  CAS  PubMed  Google Scholar 

  30. Milne RL, Ribas G, González-Neira A, Fagerholm R, Salas A, González E et al. ERCC4 associated with breast cancer risk: a two-stage case-control study using high-throughput genotyping. Cancer Res 2006; 66: 9420–9427.

    Article  CAS  PubMed  Google Scholar 

  31. Carles J, Monzo M, Amat M, Jansa S, Artells R, Navarro A, Foro P et al. Single-nucleotide polymorphisms in base excision repair, nucleotide excision repair, and double strand break genes as markers for response to radiotherapy in patients with Stage I to II head-and-neck cancer. Int J Radiat Oncol Biol Phys 2006; 66: 1022–1030.

    Article  CAS  PubMed  Google Scholar 

  32. Bacci G, Bertoni F, Longhi A, Ferrari S, Forni C, Biagini R et al. Neoadjuvant chemotherapy for high-grade central osteosarcoma of the extremity. Histologic response to preoperative chemotherapy correlates with histologic subtype of the tumor. Cancer 2003; 97: 3068–3075.

    Article  CAS  Google Scholar 

  33. Hosmer DW LS . Applied Logistic Regression. John Wiley & Sons: New York, 2000.

    Book  Google Scholar 

  34. Hosmer DW LS . Applied Survival Analysis: Regression Modeling of Time to Event Data. John Wiley & Sons: New York, 1999.

    Google Scholar 

Download references

Acknowledgements

The work was funded by FIS EC07/90305 and the Genome Spain Foundation

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Authors and Affiliations

  1. Human Genotyping Unit-CeGen, Human Cancer Genetics Programme, Spanish National Cancer Centre, Madrid, Spain

    D Caronia, R L Milne, G Pita, M R Alonso, L T Moreno, J Benítez & A González-Neira

  2. Department of Pediatrics, University of Navarra and University Clinic, Pamplona, Spain

    A Patiño-García, M Zalacain-Díez & L Sierrasesumaga-Ariznabarreta

  3. Human Genetics Group, Human Cancer Genetics Programme, Spanish National Cancer Centre, Madrid, Spain

    J Benítez

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  1. D Caronia
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Correspondence to A González-Neira.

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Caronia, D., Patiño-García, A., Milne, R. et al. Common variations in ERCC2 are associated with response to cisplatin chemotherapy and clinical outcome in osteosarcoma patients. Pharmacogenomics J 9, 347–353 (2009). https://doi.org/10.1038/tpj.2009.19

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