ERCC1 C8092A polymorphism predicts fair survival outcome in Japanese patients with pharyngo-laryngeal squamous cell carcinoma

  • Hitoshi HirakawaEmail author
  • Taro Ikegami
  • Satoe Azechi
  • Shinya Agena
  • Jin Uezato
  • Hidetoshi Kinjyo
  • Yukashi Yamashita
  • Katsunori Tanaka
  • Shunsuke Kondo
  • Hiroyuki Maeda
  • Mikio Suzuki
  • Akira Gahana
Head and Neck



To evaluate the prognostic significance of DNA excision repair gene polymorphisms, excision repair cross-complementation group 1 (ERCC1) and X-ray repair complementing defective repair in Chinese hamster cells 1 (XRCC1) polymorphisms were investigated in Japanese patients with head and neck squamous cell carcinoma (HNSCC).


A total of 225 consecutive patients with HNSCC who underwent surgery or chemoradiotherapy/radiotherapy (CRT/RT) with curative intent as primary treatment from 2006 to 2017 were recruited. ERCC1 C8092A and XRCC1 Arg399Gln polymorphisms in DNA extracted from individual blood samples were determined by the polymerase chain reaction-restriction fragment length polymorphism method. Cumulative survival was estimated by Kaplan–Meier analysis with a log-rank test and Cox proportional hazards model stratified by treatment arm, adjusting for clinical prognostic factors.


Multivariate analysis showed that carriers with the ERCC1 8092 (C/A+A/A) genotype (hazard ratio, 3.56; 95% confidence interval, 1.22–7.39; p = 0.02) had significantly worse survival than those with ERCC1 8092 C/C who received CRT/RT. Conversely, the XRCC1 Arg399Gln polymorphism did not influence survival in patients who received CRT/RT as well as surgery.


The ERCC1 C8092A polymorphism might be an independent predictor of response to CRT and survival outcome in patients with HNSCC. This is the first report to investigate the role of DNA excision repair gene polymorphisms in patients with head and neck cancer in a Japanese population.


DNA repair Single nucleotide polymorphism Survival Head and neck cancer Japanese 



This work was supported by JSPS KAKENHI Grant Number (JP17K11391) (Grant-in-Aid for Scientific Research C).


  1. 1.
    Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A (2018) Global cancer statistics 2018: gLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 68(6):394–424PubMedCrossRefGoogle Scholar
  2. 2.
    Kohno N, Kitahara S, Tamura E, Tanabe T (2002) Concurrent chemoradiotherapy with low-dose cisplatin plus 5-fluorouracil for the treatment of patients with unresectable head and neck cancer. Oncology 63(3):226–331PubMedCrossRefGoogle Scholar
  3. 3.
    Lin SS, Massa ST, Varvares MA (2016) Improved overall survival and mortality in head and neck cancer with adjuvant concurrent chemoradiotherapy in national databases. Head Neck 38(2):208–215PubMedCrossRefGoogle Scholar
  4. 4.
    Chitapanarux I, Tharavichitkul E, Lorvidhaya V, Sittitrai P, Pattarasakulchai T (2010) Induction chemotherapy with paclitaxel, ifosfamide, and cisplatin followed by concurrent chemoradiotherapy for unresectable locally advanced head and neck cancer. Biomed Imaging Interv J 6(3):e23PubMedPubMedCentralCrossRefGoogle Scholar
  5. 5.
    Jain P, Kumar P, Pai VR, Parikh PM (2008) Neoadjuvant chemotherapy or chemoradiotherapy in head and neck cancer. Indian J Cancer 45(3):83–89PubMedCrossRefGoogle Scholar
  6. 6.
    Hirakawa H, Hasegawa Y, Hanai N, Ozawa T, Hyodo I, Suzuki M (2013) Surgical site infection in clean-contaminated head and neck cancer surgery: risk factors and prognosis. Eur Arch Otorhinolaryngol 270(3):1115–1123PubMedCrossRefGoogle Scholar
  7. 7.
    Cheng L, Sturgis EM, Eicher SA, Spitz MR, Wei Q (2002) Expression of nucleotide excision repair genes and the risk for squamous cell carcinoma of the head and neck. Cancer 94(2):393–397PubMedCrossRefGoogle Scholar
  8. 8.
    Wyss AB, Weissler MC, Avery CL et al (2014) Single nucleotide polymorphisms in nucleotide excision repair genes, cancer treatment, and head and neck cancer survival. Cancer Causes Control 25(4):437–450PubMedPubMedCentralCrossRefGoogle Scholar
  9. 9.
    Sturgis EM, Dahlstrom KR, Spitz MR, Wei Q (2002) DNA repair gene ERCC1 and ERCC2/XPD polymorphisms and risk of squamous cell carcinoma of the head and neck. Arch Otolaryngol Head Neck Surg 128:1084–1088PubMedCrossRefGoogle Scholar
  10. 10.
    Goode EL, Ulrich CM, Potter JD (2002) Polymorphisms in DNA repair genes and associations with cancer risk. Cancer Epidemiol Biomark Prev 11(12):1513–1530Google Scholar
  11. 11.
    Hiyama T, Yoshihara M, Tanaka S, Chayama K (2008) Genetic polymorphisms and head and neck cancer risk (review). Int J Oncol 32(5):945–973PubMedGoogle Scholar
  12. 12.
    Lou Y, Peng WJ, Cao DS, Xie J, Li HH, Jiang ZX (2013) DNA repair gene XRCC1 polymorphisms and head and neck cancer risk: an updated meta-analysis including 16344 subjects. PLoS One 8(9):e74059PubMedPubMedCentralCrossRefGoogle Scholar
  13. 13.
    Flores-Obando RE, Gollin SM, Ragin CC (2010) Polymorphisms in DNA damage response genes and head and neck cancer risk. Biomarkers 15(5):379–399PubMedPubMedCentralCrossRefGoogle Scholar
  14. 14.
    Jun HJ, Ahn MJ, Kim HS et al (2008) ERCC1 expression as a predictive marker of squamous cell carcinoma of the head and neck treated with cisplatin-based concurrent chemoradiation. Br J Cancer 99(1):167–172PubMedPubMedCentralCrossRefGoogle Scholar
  15. 15.
    Gao Y, Liu D (2015) The roles of excision repair cross-complementation group1 in objective response after cisplatin-based concurrent chemoradiotherapy and survival in head and neck cancers: a systematic review and meta-analysis. Oral Oncol 51(6):570–577PubMedCrossRefGoogle Scholar
  16. 16.
    Bisof V, Zajc Petranovic M, Rakusic Z, Samardzic KR, Juretic A (2016) The prognostic and predictive value of excision repair cross-complementation group 1 (ERCC1) protein in 1288 patients with head and neck squamous cell carcinoma treated with platinum-based therapy: a meta-analysis. Eur Arch Otorhinolaryngol 273(9):2305–2317PubMedCrossRefGoogle Scholar
  17. 17.
    Vaezi A, Feldman CH, Niedernhofer LJ (2011) ERCC1 and XRCC1 as biomarkers for lung and head and neck cancer. Pharmgenom Pers Med 4:47–63Google Scholar
  18. 18.
    Mutlu P, Mutlu M, Yalcin S et al (2015) Detection of XRCC1 gene polymorphisms in Turkish head and neck squamous cell carcinoma patients: a comparative analysis with different populations. JBUON 20:540–547PubMedGoogle Scholar
  19. 19.
    Han Y, Liu J, Sun M, Zhang Z, Liu C, Sun Y (2016) A significant statistical advancement on the predictive values of ERCC1 polymorphisms for clinical outcomes of platinum-based chemotherapy in non-small cell lung cancer: an updated meta-analysis. Dis Markers 2016:7643981PubMedPubMedCentralGoogle Scholar
  20. 20.
    Yin M, Yan J, Voutsina A et al (2011) No evidence of an association of ERCC1 and ERCC2 polymorphisms with clinical outcomes of platinum-based chemotherapies in non-small cell lung cancer: a meta-analysis. Lung Cancer 72(3):370–377PubMedCrossRefGoogle Scholar
  21. 21.
    Quintela-Fandino M, Hitt R, Medina PP et al (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(26):4333–4339PubMedCrossRefGoogle Scholar
  22. 22.
    Geisler SA, Olshan AF, Cai J, Weissler M, Smith J, Bell D (2005) Glutathione S-transferase polymorphisms and survival from head and neck cancer. Head Neck 27(3):232–242PubMedCrossRefGoogle Scholar
  23. 23.
    Jin H, Xie X, Wang H et al (2014) ERCC1 Cys8092Ala and XRCC1 Arg399Gln polymorphisms predict progression-free survival after curative radiotherapy for nasopharyngeal carcinoma. PLoS One 9(7):e101256PubMedPubMedCentralCrossRefGoogle Scholar
  24. 24.
    Stur E, Agostini LP, Garcia FM et al (2015) Prognostic significance of head and neck squamous cell carcinoma repair gene polymorphism. Genet Mol Res 14(4):12446–12454PubMedCrossRefGoogle Scholar
  25. 25.
    Yu X, Xiao H, Zhao B, Zhang X, Wang G (2015) DNA repair gene ERCC1 C118T polymorphism predicts sensitivity of recurrent esophageal cancer to radiochemotherapy in a Chinese population. Thorac Cancer 6(6):741–748PubMedPubMedCentralCrossRefGoogle Scholar
  26. 26.
    Ding YW, Gao X, Ye DX, Liu W, Wu L, Sun HY (2015) Association of ERCC1 polymorphisms (rs3212986 and rs11615) with the risk of head and neck carcinomas based on case-control studies. Clin Transl Oncol 17(9):710–719PubMedCrossRefGoogle Scholar
  27. 27.
    Hasegawa M, Maeda H, Deng Z et al (2014) Prediction of concurrent chemoradiotherapy outcome in advanced oropharyngeal cancer. Int J Oncol 45(3):1017–1026PubMedPubMedCentralCrossRefGoogle Scholar
  28. 28.
    Yamashita Y, Ikegami T, Suzuki M et al (2019) Hypopharyngeal cancer risk in Japanese Genetic polymorphisms related to the metabolism of alcohol- and tobacco-associated carcinogens. J Cancer Res Ther 15(3):556–563PubMedCrossRefGoogle Scholar
  29. 29.
    Duell EJ, Wiencke JK, Cheng TJ et al (2000) Polymorphisms in the DNA repair genes XRCC1 and ERCC2 and biomarkers of DNA damage in human blood mononuclear cells. Carcinogenesis 21(5):965–971PubMedCrossRefGoogle Scholar
  30. 30.
    Zhou W, Gurubhagavatula S, Liu G et al (2004) 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 10(15):4939–4943PubMedCrossRefGoogle Scholar
  31. 31.
    Blasco MA, Svider PF, Raza SN et al (2017) Systemic therapy for head and neck squamous cell carcinoma: historical perspectives and recent breakthroughs. Laryngoscope 127(11):2565–2569PubMedCrossRefGoogle Scholar
  32. 32.
    Wolf GT, Fisher SG, Hong WK et al (1991) Induction chemotherapy plus radiation compared with surgery plus radiation in patients with advanced laryngeal cancer. N Engl J Med 324(24):1685–1690PubMedCrossRefGoogle Scholar
  33. 33.
    Lefebvre JL, Chevalier D, Luboinski B, Kirkpatrick A, Collette L, Sahmoud T (1996) Larynx preservation in pyriform sinus cancer: preliminary results of a European Organization for Research and Treatment of Cancer phase III trial. EORTC Head and Neck Cancer Cooperative Group. J Natl Cancer Inst 88(13):890–899PubMedCrossRefGoogle Scholar
  34. 34.
    Pignon JP, le Maitre A, Maillard E, Bourhis J, Group M-NC (2009) Meta-analysis of chemotherapy in head and neck cancer (MACH-NC): an update on 93 randomised trials and 17,346 patients. Radiother Oncol 92(1):4–14CrossRefGoogle Scholar
  35. 35.
    Schena M, Guarrera S, Buffoni L et al (2012) DNA repair gene expression level in peripheral blood and tumour tissue from non-small cell lung cancer and head and neck squamous cell cancer patients. DNA Repair (Amst) 11(4):374–380CrossRefGoogle Scholar
  36. 36.
    Yoon SM, Hong YC, Park HJ et al (2005) The polymorphism and haplotypes of XRCC1 and survival of non-small-cell lung cancer after radiotherapy. Int J Radiat Oncol Biol Phys 63(3):885–891PubMedCrossRefGoogle Scholar
  37. 37.
    Petty WJ, Knight SN, Mosley L et al (2007) A pharmacogenomic study of docetaxel and gemcitabine for the initial treatment of advanced non-small cell lung cancer. J Thorac Oncol 2(3):197–202PubMedCrossRefGoogle Scholar
  38. 38.
    Wang Z, Xu B, Lin D et al (2008) XRCC1 polymorphisms and severe toxicity in lung cancer patients treated with cisplatin-based chemotherapy in Chinese population. Lung Cancer 62(1):99–104PubMedCrossRefGoogle Scholar
  39. 39.
    Andrew AS, Nelson HH, Kelsey KT et al (2006) Concordance of multiple analytical approaches demonstrates a complex relationship between DNA repair gene SNPs, smoking and bladder cancer susceptibility. Carcinogenesis 27(5):1030–1037PubMedCrossRefGoogle Scholar
  40. 40.
    Yang P, Ho JW, Zomaya AY, Zhou BB (2010) A genetic ensemble approach for gene-gene interaction identification. 29(11):524Google Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  • Hitoshi Hirakawa
    • 1
    Email author
  • Taro Ikegami
    • 1
  • Satoe Azechi
    • 2
  • Shinya Agena
    • 1
  • Jin Uezato
    • 1
  • Hidetoshi Kinjyo
    • 1
  • Yukashi Yamashita
    • 1
  • Katsunori Tanaka
    • 1
  • Shunsuke Kondo
    • 1
  • Hiroyuki Maeda
    • 1
  • Mikio Suzuki
    • 1
  • Akira Gahana
    • 1
    • 3
  1. 1.Department of Otorhinolaryngology, Head and Neck Surgery, Graduate School of MedicineUniversity of the RyukyusOkinawaJapan
  2. 2.School of MedicineTokai UniversityIseharashiJapan
  3. 3.Department of Otorhinolaryngology-Head and Neck SurgeryUniversity of MiyazakiMiyazakiJapan

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