Journal of Gastrointestinal Surgery

, Volume 13, Issue 8, pp 1411–1421 | Cite as

ERCC1 and XRCC1 Gene Polymorphisms Predict Response to Neoadjuvant Radiochemotherapy in Esophageal Cancer

  • Ute Warnecke-Eberz
  • Daniel Vallböhmer
  • Hakan Alakus
  • Fabian Kütting
  • Georg Lurje
  • Elfriede Bollschweiler
  • Anke Wienand-Dorweiler
  • Uta Drebber
  • Arnulf H. Hölscher
  • Ralf Metzger
Original Article



Neoadjuvant treatment strategies have been developed to improve survival of patients with locally advanced esophageal cancer. Since only patients with major histopathological response benefit from this therapy, predictive markers are needed. We examined a panel of selected gene polymorphisms to predict response to neoadjuvant radiochemotherapy (cisplatin, 5-fluorouracil, 36 Gy) in esophageal cancer patients.

Materials and method

Genomic DNA was extracted from paraffin-embedded tissues of 52 patients. Allelic genotyping was performed by real-time polymerase chain reaction using allele-specific TaqMan probes and correlated with therapy response.


Single-nucleotide polymorphism ERCC1 C118T was predictive for therapy response (p < 0.003). Within the TT genotype group of 25 patients, 20 (80%) did not respond to chemoradiation. Of 20 patients with heterogeneous C/T genotype, 14 (70%) were major responders. The CC genotype (seven patients) was not of predictive importance. ERCC1 polymorphism was significantly (p < 0.02) associated with formation of lymph node metastases. Predominant GG genotype of XRCC1 A194G was not predictive; however, the rarely occurring AA genotype was response-associated and the A/G variant was associated with nonresponse. Fifteen additionally analyzed polymorphisms did not show any correlation.


Our data support the role of ERCC1 as a predictive marker for therapy response. Single-nucleotide polymorphisms of ERCC1 and XRCC1 could be applied to further individualize treatment strategies.


Single-nucleotide polymorphism Nucleotide excision repair Multimodality treatment Chemo-radio-sensitivity Response prediction 


  1. 1.
    Jemal A, Siegel R, Ward E, Murray T, Xu J, Thun MJ. Cancer statistics 2007. CA Cancer J Clin 2007;57:43–66. doi:10.3322/canjclin.57.1.43.CrossRefPubMedGoogle Scholar
  2. 2.
    Rouvelas I, Zeng W, Lindblad M, Viklund P, Ye W, Lagergren J. Survival after surgery for oesophageal cancer: a population-based study. Lancet Oncol 2005;6:864–870. doi:10.1016/S1470-2045(05)70347-8.CrossRefPubMedGoogle Scholar
  3. 3.
    Sherman CA, Turrisi AT, Wallace MB, Reed CE. Locally advanced esophageal cancer. Curr Treat Options Oncol 2002;3:475–485. doi:10.1007/s11864-002-0067-3.CrossRefPubMedGoogle Scholar
  4. 4.
    Leichman CG, Benedetti JK, Zalupski MM, Hochster H, Shields AF, Lenz HJ, Wade Iii IL, Bearden Iii JD, Macdonald JS. Assessment of infusional 5-fluorouracil schedule and dose intensity: a Southwest Oncology Group and Eastern Cooperative Oncology Group study. Clin Colorectal Cancer 2004;5:119–123. doi:10.3816/CCC.2005.n.024.CrossRefGoogle Scholar
  5. 5.
    Kaklamanos I, Walker G, Ferry K, Franceschi D, Livingstone AS. Neoadjuvant treatment for respectable cancer of the esophagus and the gastroesophageal junction: a meta-analysis of randomized clinical trials. Ann Surg Oncol 2003;10:754–761. doi:10.1245/ASO.2003.03.078.CrossRefPubMedGoogle Scholar
  6. 6.
    Urschel J, Vasan H. A meta-analysis of randomized controlled trials that compared neoadjuvant chemoradiation and surgery to surgery alone for respectable esophageal cancer. Am J Surg 2003;185:538–543. doi:10.1016/S0002-9610(03)00066-7.CrossRefPubMedGoogle Scholar
  7. 7.
    Fiorica F, Di BD, Schepis F, Licata A, Shahied L, Venturi A, Falchi AM, Cramma C. Preoperative chemoradiotherapy for oesophageal cancer: a systematic review and meta-analysis. Gut 2004;53:925–930. doi:10.1136/gut.2003.025080.CrossRefPubMedGoogle Scholar
  8. 8.
    Gebski V, Burmeister B, Smithers BM, Foo K, Zalcberg J, Simes J. Australasian Gastro-Intestinal Trials Group. Survival benefits from neoadjuvant chemoradiotherapy or chemotherapy in oesophageal carcinoma: a meta-analysis. Lancet Oncol 2007;8:226–234. doi:10.1016/S1470-2045(07)70039-6.CrossRefPubMedGoogle Scholar
  9. 9.
    Schneider PM, Baldus SE, Metzger R, Kocher M, Bongartz R, Bollschweiler E, Schaefer H, Thiele J, Dienes HP, Mueller RP, Hoelscher AH. Histomorphologic tumor regression and lymph node metastases determine prognosis following neoadjuvant radiochemotherapy for esophageal cancer: implications for response classification. Ann Surg 2005;242:684–692. doi:10.1097/01.sla.0000186170.38348.7b.CrossRefPubMedGoogle Scholar
  10. 10.
    Glinsky GV. Integration of HapMap-based SNP pattern analysis and gene expression profiling reveals common SNP profiles for cancer therapy outcome predictor genes. Cell Cycle 2006;5:2613–2625.PubMedGoogle Scholar
  11. 11.
    Mei R, Galipeau PC, Prass C, Berno A, Ghandour G, Patil N, Wolff RK, Chee MS, Reis BJ, Lockhart DJ. Genome-wide detection of allelic imbalance using human SNPs and high-density DNA arrays. Genome Res 2000;10:1126–1137. doi:10.1101/gr.10.8.1126.CrossRefPubMedGoogle Scholar
  12. 12.
    Hu N, Wang C, Hu Y, Yang HH, Kong LH, Lu N, Su H, Wang QH, Goldstein AM, Buetow KH, Emmert-Buck MR, Taylor PR, Lee MP. Genome-wide loss of heterozygosity and copy number alteration in esophageal squamous cell carcinoma using the Affymetrix gene chip mapping 10 K array. BMC Genomics 2006;7:299–315. doi:10.1186/1471-2164-7-299.CrossRefPubMedGoogle Scholar
  13. 13.
    Ford BN, Ruttan CC, Kyle VL, Brackley ME, Glickman BW. Identification of single nucleotide polymorphisms in human DNA repair genes. Carcinogenesis 2000;11:1977–1981. doi:10.1093/carcin/21.11.1977.CrossRefGoogle Scholar
  14. 14.
    Goode EL, Ulrich MC, Potter JD. Polymorphisms in DNA repair genes and associations with cancer risk. Cancer Epidemiol Biomarkers Prev 2002;11:1513–1530.PubMedGoogle Scholar
  15. 15.
    Ulrich CM, Robien K, McLeod HL. Cancer pharmacogenetics: polymorphisms, pathways and beyond. Nat Rev Cancer 2003;3:912–920. doi:10.1038/nrc1233.CrossRefPubMedGoogle Scholar
  16. 16.
    Junker K, Thomas M, Schulmann K, Klinke F, Bosse U, Müller KM. Tumour regression in non-small-cell lung cancer following neoadjuvant therapy. Histological assessment. J Cancer Res Clin Oncol 1997;123:469–477. doi:10.1007/BF01192200.CrossRefPubMedGoogle Scholar
  17. 17.
    Baldus SE, Mönig SP, Schröder W, et al. Regression of oesophageal carcinomas after neoadjuvant radiochemotherapy: criteria of the histopathological evaluation. Pathologe 2004;25:4780–4788.CrossRefGoogle Scholar
  18. 18.
    Cox DG, Hankinson SE, Hunter DJ. The erbB2/HER2/neu receptor polymorphism Ile655Val and breast cancer risk. Pharmacogenet Genomics 2005;15:477–450. doi:10.1097/01.fpc.0000166822.66754.c6.CrossRefGoogle Scholar
  19. 19.
    Moreno V, Gemignani F, Landi S, Gioia-Patricola L, Chabrier A, Blanco I, Gonzalez S, Capella G, Canzian F, Bellvitge Colorectal Cancer Study Group. Polymorphisms in genes of nucleotide and base excision repair: risk and prognosis of colorectal cancer. Clin Cancer Res 2006;12:2101–2108. doi:10.1158/1078-0432.CCR-05-1363.CrossRefPubMedGoogle Scholar
  20. 20.
    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;10:4939–4943. doi:10.1158/1078-0432.CCR-04-0247.CrossRefPubMedGoogle Scholar
  21. 21.
    Wu X, Gu J, Wu T/T, Swisher SG, Liao Y, Correa AM, Liu J, Etyel CJ, Amos CI, Huang M, Chiang SS, Milas L, Hittelman WN, Ajani JA. Genetic variations in radiation and chemotherapy drug action pathways predict clinical outcomes in esophageal cancer. J Clin Oncol 2006;14:3789–3798. doi:10.1200/JCO.2005.03.6640.CrossRefGoogle Scholar
  22. 22.
    Gordon MA, Gil J, Lu B, Zhang W, Yang D, Yun J, Schneider S, Grosherr S, Iqbal S, Press OA, Rhodes K, Lenz HJ. Genomic profiling associated with recurrence in patients with rectal cancer treated with chemoradiation. Pharmacogenomics 2006;7:67–88. doi:10.2217/14622416.7.1.67.CrossRefPubMedGoogle Scholar
  23. 23.
    Terrazzino S, Agostini M, Pucciarelli S, Pasetto LM, Friso ML, Ambrosi A, Lisi V, Leon A, Lise M, Nitti D. A haplotype of the methylenetetrahydrofolate reductase gene predicts poor tumor response in rectal cancer patients receiving preoperative chemoradiation. Pharmacogenet Genomics 2006;16:817–824. doi:10.1097/01.fpc.0000230412.89973.c0.CrossRefPubMedGoogle Scholar
  24. 24.
    Dong ZM, Cui YJ, Kuang G, Wang R, Yu FL, Zhang JH. Polymorphisms of thymidylate synthase gene and correlation of its protein expression to lymph node metastasis of esophageal squamous cell carcinoma. Ai Zheng 2005;24:1225–1229.PubMedGoogle Scholar
  25. 25.
    Morganti M, Ciantelli M, Giglioni B, Putignano AL, Nobili S, Papi L, Landini I, Napoli C, Valanzano R, Cianchi F, Boddi V, Tonelli F, Cortesini C, Mazzei T, Genuardi M, Mini E. Relationships between promoter polymorphisms in the thymidylate synthase gene and mRNA levels in colorectal cancers. Eur J Cancer 2005;41:2176–2183. doi:10.1016/j.ejca.2005.06.016.CrossRefPubMedGoogle Scholar
  26. 26.
    Marcuello E, Altés A, del Rio E, César A, Menoyokj A, Baiget M. Single nucleotide polymorphism in the 5’ tandem repeat sequences of thymidylate synthase gene predicts for response to fluorouracil-based chemotherapy in advanced colorectal cancer patients. Int J Cancer 2004;112:733–737. doi:10.1002/ijc.20487.CrossRefPubMedGoogle Scholar
  27. 27.
    Takehara A, Kawakami K, Ohta N, Oyama K, Ota Y, ‘Oda M, Watqanbe G. Prognostic significance of the polymorphisms in thymidylate synthase and methylenetetrahydrofolate reductase gene in lung cancer. Anticancer Res 2005;25:4455–4461.PubMedGoogle Scholar
  28. 28.
    Chung HH, Kim MK, Kim JW, Park NH, Song YS, Kang SB, Lee HP. XRCC1 R399Q polymorphisms associated with response to platinum-based neoadjuvant chemotherapy in bulky cervical cancer. Gynecol Oncol 2006;103:1031–1037. doi:10.1016/j.ygyno.2006.06.016.CrossRefPubMedGoogle Scholar
  29. 29.
    Bollschweiler E. Benefits and limitations of Kaplan–Meier calculations of survival chance in cancer surgery. Langenbecks Arch Surg 2003;388:239–244. doi:10.1007/s00423-003-0410-6.CrossRefPubMedGoogle Scholar
  30. 30.
    Kaplan EL, Meier P. Nonparametric estimation from incomplete observations. J Am Stat Assoc 1958;53:457–481. doi:10.2307/2281868.CrossRefGoogle Scholar
  31. 31.
    Pocock SJ, Clayton TC, Altman DG. Survival plots of time-to-event outcomes in clinical trials: good practice and pitfalls. Lancet 2002;359:1686–1689. doi:10.1016/S0140-6736(02)08594-X.CrossRefPubMedGoogle Scholar
  32. 32.
    Westerterp M, van Westreenen HL, Reitsma JB, Hoekstra OS, Stoker J, Fockens P, Jager PL, Van Eck-Smit BL, Plukker JT, van Lanschot JJ, Sloof GW. Esophageal cancer: CT, endoscopic US, and FDG PET for assessment of response to neoadjuvant therapy—systematic review. Radiology 2005;236:841–851. doi:10.1148/radiol.2363041042.CrossRefPubMedGoogle Scholar
  33. 33.
    Reed E. Platinum-DNA adduct, nucleotide excision repair and platinum based anti-cancer chemotherapy. Cancer Treat Rev 1998;24:331–344. doi:10.1016/S0305-7372(98)90056-1.CrossRefPubMedGoogle Scholar
  34. 34.
    Wood RD, Mitchell M, Sgouros J, Lindahl T. Human DNA repair genes. Sci Walsh DC 2001;291:1284–1289. doi:10.1126/science.1056154.CrossRefGoogle Scholar
  35. 35.
    You JS, Wang M, Lee SH. Biochemical analysis of damage recognition process in nucleotide excision process in nucleotide excision repair. J Biol Chem 2003;278:7476–74785. doi:10.1074/jbc.M210603200.CrossRefPubMedGoogle Scholar
  36. 36.
    Gurubhagavatula S, Siu 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;22:2594–2601. doi:10.1200/JCO.2004.08.067.CrossRefPubMedGoogle Scholar
  37. 37.
    Improta G, Sgambato A, Bianchino G, Zup A, Grieco V, La Torre G, Traficante A, Cittadini A. 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 2008;28:2941–2946.PubMedGoogle Scholar
  38. 38.
    Hiyama T, Yoshihara M, Tanaka S, Chayama K. Genetic polymorphisms and head and neck cancer risk. Int J Oncol 2008;32:945–973. Review.PubMedGoogle Scholar
  39. 39.
    Su D, Ma S, Liu P, Jiang Z, Lv W, Zhang Y, Deng Q, Smith S, Yu H. Genetic polymorphisms and treatment response in advanced non-small cell lung cancer. Lung Cancer 2007;56:281–288. doi:10.1016/j.lungcan.2006.12.002.CrossRefPubMedGoogle Scholar
  40. 40.
    Kang S, Ju W, Kim JW, Park NH, Song YS, Kim SC, Park SY, Kang SB, Lee HP. Association between excision repair cross-complementation group 1 polymorphism and clinical outcome of platinum-based chemotherapy in patients with epithelial ovarian cancer. Exp Mol Med 2006;38:320–324.PubMedGoogle Scholar
  41. 41.
    Steffensen KD, Waldstrom M, Jeppesen U, Brandslund I, Jakobsen A. Prediction of response to chemotherapy by ERCC1 immunohistochemistry and ERCC1 polymorphism in ovarian cancer. Int J Gynecol Cancer 2008;18:702–710. doi:10.1111/j.1525-1438.2007.01068.x.CrossRefPubMedGoogle Scholar
  42. 42.
    Viguier J, Boige V, Miquel C, Pocard M, Giraudeau B, Sabourin JC, Ducreaux M, Sarasin A, Praz F. ERCC1 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 2003;11:6212–6217. doi:10.1158/1078-0432.CCR-04-2216.CrossRefGoogle Scholar
  43. 43.
    Stoehlmacher J, Park DJ, Zhang W, Yang D, Groshen S, Zahedy S, Lenz HJ. 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.PubMedGoogle Scholar
  44. 44.
    Paré L, Marcuello E, Altés A, del Rio E, Sedano K, Salazar J, Cortés A, Barnadas A, Baiget M. Pharmacogenetic prediction of clinical outcome in advanced colorectal cancer patients receiving oxaliploatin/5-fluorouracdil as first-line chemotherapy. Br J Cancer 2008;99:1050–1055. doi:10.1038/sj.bjc.6604671.CrossRefPubMedGoogle Scholar
  45. 45.
    Warnecke-Eberz U, Metzger R, Miyazono F, Baldus SE, Neiss S, Brabender J, Schaefer H, Doerfler W, Bollschweiler E, Dienes HP, Mueller RP, Danenberg PV, Hoelscher AH, Schneider PM. High specificity of quantitative excision repair cross-complementing 1 messenger RNA expression for prediction of minor histopathological response to neoadjuvant radiochemotherapy in esophageal cancer. Clin Cancer Res 2004;10:3794–3799. doi:10.1158/1078-0432.CCR-03-0079.CrossRefPubMedGoogle Scholar
  46. 46.
    Metzger R, Leichman CG, Danenberg KD, Danenerg PV, Lenz HJ, Hayashi K, Groshen S, Salonga D, Cohen H, Laine L, Crookes P, Silberman H, Baranda J, Konda B, Leichman L. ERCC1 mRNA levels complement thymidylate synthase mRNA levels in predicting response and survival for gastric cancer patients receiving combination cisplatin and fluorouracil chemotherapy. J Clin Oncol 1998;16:309–316.PubMedGoogle Scholar
  47. 47.
    Leichmann L, Lawrence D, Leichman CG, Nava H, Nava E, Proulx G, Clark K, Khushalani NI, Berdzik J, Greco W, Smith P, Creaven PJ, Kepner JL, Javle MM, Pendyala L. Expression of genes related to activity of oxaliplatin and 5-fluorouracil in endoscopic biopsies of primary esophageal cancer in patients receiving oxaliplatin, 5-flourouracil and radiation: characterization and exploratory analysis with survival. J Chemother 2006;18:514–524.Google Scholar
  48. 48.
    Altaha R, Liang X, Yu JJ, Reed E. Excision repair cross complementing-group 1: gene expression and platinum resistance. Int J Mol Med 2004;14:959–970.PubMedGoogle Scholar
  49. 49.
    Park DJ, Lenz HJ. Determinants of chemosensitivity in gastric cancer. Curr Opin Pharmacol 2006;6:337–344. doi:10.1016/j.coph.2006.05.002.CrossRefPubMedGoogle Scholar
  50. 50.
    Brabender J, Vallböhmer D, Grimminger P, Hoffmann AC, Ling F, Lurje G, Bollschweiler E, Schneider PM, Hölscher AH, Metzger R. J Gastrointest Surg 2008;12:1815–1821. doi:10.1007/s11605-008-0668-7.CrossRefPubMedGoogle Scholar
  51. 51.
    Kim KM, Cho KJ, Kwon GY, Park SI, Kim YH, Kim JH, Song HY, Shin JH, Jung HY, Lee GH, Coi KD, Kim SB. Patients with ERCC1-negative locally advanced esophageal cancers may benefit from preoperative chemoradiotherapy. Clin Cancer Res 2008;14:4225–4231. doi:10.1158/1078-0432.CCR-07-4848.CrossRefPubMedGoogle Scholar
  52. 52.
    Gossage L, Madhusudan S. Current status of excision repair cross complementing-group 1 (ERCC1) in cancer. Cancer Treat Rev 2007;33:565–577. doi:10.1016/j.ctrv.2007.07.001.CrossRefPubMedGoogle Scholar

Copyright information

© The Society for Surgery of the Alimentary Tract 2009

Authors and Affiliations

  • Ute Warnecke-Eberz
    • 1
  • Daniel Vallböhmer
    • 1
  • Hakan Alakus
    • 1
  • Fabian Kütting
    • 1
  • Georg Lurje
    • 1
  • Elfriede Bollschweiler
    • 1
  • Anke Wienand-Dorweiler
    • 1
  • Uta Drebber
    • 2
  • Arnulf H. Hölscher
    • 1
  • Ralf Metzger
    • 1
  1. 1.Department of General, Visceral, and Cancer Surgery, Center for Integrated OncologyUniversity Hospital of CologneCologneGermany
  2. 2.Institute of Pathology, Center for Integrated OncologyUniversity Hospital of CologneCologneGermany

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