Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Article
  • Published:

AGXT and ERCC2 polymorphisms are associated with clinical outcome in metastatic colorectal cancer patients treated with 5-FU/oxaliplatin

The Pharmacogenomics Journal volume 16, pages 272–279 (2016)Cite this article

Subjects

Abstract

The objective of the study was to investigate whether specific single nucleotide polymorphisms (SNPs) with influence on drug transport, biotransformation and repair mechanisms are associated with treatment outcome and toxicity in metastatic colorectal cancer (mCRC). We genotyped blood samples from 519 mCRC patients treated with first-line 5-fluorouracil and oxaliplatin +/− cetuximab for 17 SNPs in 10 genes involved in membrane transport (ABCC1 and ABCC2), drug biotransformation (GSTP1 and AGXT) and DNA repair (ERCC1, ERCC2, XRCC1, XRCC3, XPG and MSH6). The AGXT-rs34116584 and the ERCC2-rs238406 polymorphisms were significantly associated with progression-free survival (P=0.002 and P=0.001, respectively). Associations between 18 toxicity variables and SNPs were identified, although none were significant after Bonferroni correction for multiple comparisons. The study identified SNPs of potential use as markers of clinical outcome in oxaliplatin-treated mCRC patients. If validated in other studies, they could improve the selection of therapy in mCRC.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1

Similar content being viewed by others

References

  1. Cunningham D, Atkin W, Lenz HJ, Lynch HT, Minsky B, Nordlinger B et al. Colorectal cancer. Lancet 2010; 375: 1030–1047.

    Article  PubMed  Google Scholar 

  2. de GA, Figer A, Seymour M, Homerin M, Hmissi A, Cassidy J et al. Leucovorin and fluorouracil with or without oxaliplatin as first-line treatment in advanced colorectal cancer. J Clin Oncol 2000; 18: 2938–2947.

    Article  Google Scholar 

  3. Jensen NF, Smith DH, Nygard SB, Romer MU, Nielsen KV, Brunner N . Predictive biomarkers with potential of converting conventional chemotherapy to targeted therapy in patients with metastatic colorectal cancer. Scand J Gastroenterol 2012; 47: 340–355.

    Article  CAS  PubMed  Google Scholar 

  4. Ibrahim A, Hirschfeld S, Cohen MH, Griebel DJ, Williams GA, Pazdur R . FDA drug approval summaries: oxaliplatin. Oncologist 2004; 9: 8–12.

    Article  PubMed  Google Scholar 

  5. Benhaim L, Labonte MJ, Lenz HJ . Pharmacogenomics and metastatic colorectal cancer: current knowledge and perspectives. Scand J Gastroenterol 2012; 47: 325–339.

    Article  CAS  PubMed  Google Scholar 

  6. Cortejoso L, Lopez-Fernandez LA . Pharmacogenetic markers of toxicity for chemotherapy in colorectal cancer patients. Pharmacogenomics 2012; 13: 1173–1191.

    Article  CAS  PubMed  Google Scholar 

  7. Strimpakos AS, Syrigos KN, Saif MW . Pharmacogenetics and biomarkers in colorectal cancer. Pharmacogenomics J 2009; 9: 147–160.

    Article  CAS  PubMed  Google Scholar 

  8. Shirota Y, Stoehlmacher J, Brabender J, Xiong YP, Uetake H, Danenberg KD et al. ERCC1 and thymidylate synthase mRNA levels predict survival for colorectal cancer patients receiving combination oxaliplatin and fluorouracil chemotherapy. J Clin Oncol 2001; 19: 4298–4304.

    Article  CAS  PubMed  Google Scholar 

  9. Grimminger PP, Shi M, Barrett C, Lebwohl D, Danenberg KD, Brabender J et al. TS and ERCC-1 mRNA expressions and clinical outcome in patients with metastatic colon cancer in CONFIRM-1 and -2 clinical trials. Pharmacogenomics J 2012; 12: 404–411.

    Article  CAS  PubMed  Google Scholar 

  10. Chang IY, Kim MH, Kim HB, Lee DY, Kim SH, Kim HY et al. Small interfering RNA-induced suppression of ERCC1 enhances sensitivity of human cancer cells to cisplatin. Biochem Biophys Res Commun 2005; 327: 225–233.

    Article  CAS  PubMed  Google Scholar 

  11. Chang PM, Tzeng CH, Chen PM, Lin JK, Lin TC, Chen WS et al. ERCC1 codon 118 C–>T polymorphism associated with ERCC1 expression and outcome of FOLFOX-4 treatment in Asian patients with metastatic colorectal carcinoma. Cancer Sci 2009; 100: 278–83.

    Article  CAS  PubMed  Google Scholar 

  12. Chen YC, Tzeng CH, Chen PM, Lin JK, Lin TC, Chen WS et al. Influence of GSTP1 I105V polymorphism on cumulative neuropathy and outcome of FOLFOX-4 treatment in Asian patients with colorectal carcinoma. Cancer Sci 2010; 101: 530–535.

    Article  CAS  PubMed  Google Scholar 

  13. Huang MY, Huang ML, Chen MJ, Lu CY, Chen CF, Tsai PC et al. Multiple genetic polymorphisms in the prediction of clinical outcome of metastatic colorectal cancer patients treated with first-line FOLFOX-4 chemotherapy. Pharmacogenet Genomics 2011; 21: 18–25.

    Article  CAS  PubMed  Google Scholar 

  14. Ruzzo A, Graziano F, Loupakis F, Rulli E, Canestrari E, Santini D et al. Pharmacogenetic profiling in patients with advanced colorectal cancer treated with first-line FOLFOX-4 chemotherapy. J Clin Oncol 2007; 25: 1247–1254.

    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. Park DJ, Zhang W, Stoehlmacher J, Tsao-Wei D, Groshen S, Gil J et al. ERCC1 gene polymorphism as a predictor for clinical outcome in advanced colorectal cancer patients treated with platinum-based chemotherapy. Clin Adv Hematol Oncol 2003; 1: 162–166.

    PubMed  Google Scholar 

  17. Yin M, Yan J, Martinez-Balibrea E, Graziano F, Lenz HJ, Kim HJ et al. ERCC1 and ERCC2 polymorphisms predict clinical outcomes of oxaliplatin-based chemotherapies in gastric and colorectal cancer: a systemic review and meta-analysis. Clin Cancer Res 2011; 17: 1632–1640.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Pare L, Marcuello E, Altes A, del RE, Sedano L, Salazar J et al. Pharmacogenetic prediction of clinical outcome in advanced colorectal cancer patients receiving oxaliplatin/5-fluorouracil as first-line chemotherapy. Br J Cancer 2008; 99: 1050–1055.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Viguier J, Boige V, Miquel C, Pocard M, Giraudeau B, Sabourin JC et al. 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 2005; 11: 6212–6217.

    Article  CAS  PubMed  Google Scholar 

  20. Lee KH, Chang HJ, Han SW, Oh DY, Im SA, Bang YJ et al. Pharmacogenetic analysis of adjuvant FOLFOX for Korean patients with colon cancer. Cancer Chemother Pharmacol 2013; 71: 843–851.

    Article  CAS  PubMed  Google Scholar 

  21. Inada M, Sato M, Morita S, Kitagawa K, Kawada K, Mitsuma A et al. Associations between oxaliplatin-induced peripheral neuropathy and polymorphisms of the ERCC1 and GSTP1 genes. Int J Clin Pharmacol Ther 2010; 48: 729–734.

    Article  CAS  PubMed  Google Scholar 

  22. Kweekel DM, Gelderblom H, Guchelaar HJ . Pharmacology of oxaliplatin and the use of pharmacogenomics to individualize therapy. Cancer Treat Rev 2005; 31: 90–105.

    Article  CAS  PubMed  Google Scholar 

  23. Stoehlmacher J, Park DJ, Zhang W, Groshen S, Tsao-Wei DD, Yu MC et al. Association between glutathione S-transferase P1, T1, and M1 genetic polymorphism and survival of patients with metastatic colorectal cancer. J Natl Cancer Inst 2002; 94: 936–942.

    Article  CAS  PubMed  Google Scholar 

  24. McLeod HL, Sargent DJ, Marsh S, Green EM, King CR, Fuchs CS et al. Pharmacogenetic predictors of adverse events and response to chemotherapy in metastatic colorectal cancer: results from North American Gastrointestinal Intergroup Trial N9741. J Clin Oncol 2010; 28: 3227–3233.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Watson MA, Stewart RK, Smith GB, Massey TE, Bell DA . Human glutathione S-transferase P1 polymorphisms: relationship to lung tissue enzyme activity and population frequency distribution. Carcinogenesis 1998; 19: 275–280.

    Article  CAS  PubMed  Google Scholar 

  26. Lecomte T, Landi B, Beaune P, Laurent-Puig P, Loriot MA . Glutathione S-transferase P1 polymorphism (Ile105Val) predicts cumulative neuropathy in patients receiving oxaliplatin-based chemotherapy. Clin Cancer Res 2006; 12: 3050–3056.

    Article  CAS  PubMed  Google Scholar 

  27. Kanai M, Yoshioka A, Tanaka S, Nagayama S, Matsumoto S, Nishimura T et al. Associations between glutathione S-transferase pi Ile105Val and glyoxylate aminotransferase Pro11Leu and Ile340Met polymorphisms and early-onset oxaliplatin-induced neuropathy. Cancer Epidemiol 2010; 34: 189–193.

    Article  CAS  PubMed  Google Scholar 

  28. Boige V, Mendiboure J, Pignon JP, Loriot MA, Castaing M, Barrois M et al. Pharmacogenetic assessment of toxicity and outcome in patients with metastatic colorectal cancer treated with LV5FU2, FOLFOX, and FOLFIRI: FFCD 2000-05. J Clin Oncol 2010; 28: 2556–2564.

    Article  CAS  PubMed  Google Scholar 

  29. Etienne-Grimaldi MC, Milano G, Maindrault-Goebel F, Chibaudel B, Formento JL, Francoual M et al. Methylenetetrahydrofolate reductase (MTHFR) gene polymorphisms and FOLFOX response in colorectal cancer patients. Br J Clin Pharmacol 2010; 69: 58–66.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Braun MS, Richman SD, Thompson L, Daly CL, Meade AM, Adlard JW et al. Association of molecular markers with toxicity outcomes in a randomized trial of chemotherapy for advanced colorectal cancer: the FOCUS trial. J Clin Oncol 2009; 27: 5519–5528.

    Article  CAS  PubMed  Google Scholar 

  31. Kweekel DM, Gelderblom H, Antonini NF, van der ST, Nortier JW, Punt CJ et al. Glutathione-S-transferase pi (GSTP1) codon 105 polymorphism is not associated with oxaliplatin efficacy or toxicity in advanced colorectal cancer patients. Eur J Cancer 2009; 45: 572–578.

    Article  CAS  PubMed  Google Scholar 

  32. Cavaletti G, Alberti P, Marmiroli P . Chemotherapy-induced peripheral neurotoxicity in the era of pharmacogenomics. Lancet Oncol 2011; 12: 1151–1161.

    Article  CAS  PubMed  Google Scholar 

  33. Gamelin L, Capitain O, Morel A, Dumont A, Traore S, Anne LB et al. Predictive factors of oxaliplatin neurotoxicity: the involvement of the oxalate outcome pathway. Clin Cancer Res 2007; 13: 6359–6368.

    Article  CAS  PubMed  Google Scholar 

  34. Cecchin E, D’Andrea M, Lonardi S, Zanusso C, Pella N, Errante D et al. A prospective validation pharmacogenomic study in the adjuvant setting of colorectal cancer patients treated with the 5-fluorouracil/leucovorin/oxaliplatin (FOLFOX4) regimen. Pharmacogenomics J 2013; 13: 403–409.

    Article  CAS  PubMed  Google Scholar 

  35. Huang L, Wang C, Zheng W, Liu R, Yang J, Tang C . Effects of celecoxib on the reversal of multidrug resistance in human gastric carcinoma by downregulation of the expression and activity of P-glycoprotein. Anticancer Drugs 2007; 18: 1075–1080.

    Article  CAS  PubMed  Google Scholar 

  36. Theile D, Grebhardt S, Haefeli WE, Weiss J . Involvement of drug transporters in the synergistic action of FOLFOX combination chemotherapy. Biochem Pharmacol 2009; 78: 1366–1373.

    Article  CAS  PubMed  Google Scholar 

  37. Tveit KM, Guren T, Glimelius B, Pfeiffer P, Sorbye H, Pyrhonen S et al. Phase III trial of cetuximab with continuous or intermittent fluorouracil, leucovorin, and oxaliplatin (Nordic FLOX) versus FLOX alone in first-line treatment of metastatic colorectal cancer: the NORDIC-VII study. J Clin Oncol 2012; 30: 1755–1762.

    Article  CAS  PubMed  Google Scholar 

  38. Therasse P, Arbuck SG, Eisenhauer EA, Wanders J, Kaplan RS, Rubinstein L et al. 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: 205–216.

    Article  CAS  PubMed  Google Scholar 

  39. Napolioni V . The relevance of checking population allele frequencies and Hardy-Weinberg Equilibrium in genetic association studies: the case of SLC6A4 5-HTTLPR polymorphism in a Chinese Han Irritable Bowel Syndrome association study. Immunol Lett 2014; 162: 276–278.

    Article  CAS  PubMed  Google Scholar 

  40. Purdue PE, Takada Y, Danpure CJ . Identification of mutations associated with peroxisome-to-mitochondrion mistargeting of alanine/glyoxylate aminotransferase in primary hyperoxaluria type 1. J Cell Biol 1990; 111: 2341–2351.

    Article  CAS  PubMed  Google Scholar 

  41. Johnson AD, Handsaker RE, Pulit SL, Nizzari MM, O'Donnell CJ, de Bakker PI . SNAP: a web-based tool for identification and annotation of proxy SNPs using HapMap. Bioinformatics 2008; 24: 2938–2939.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Pey AL, Albert A, Salido E . Protein homeostasis defects of alanine-glyoxylate aminotransferase: new therapeutic strategies in primary hyperoxaluria type I. Biomed Res Int 2013; 2013: 687658.

    Article  PubMed  PubMed Central  Google Scholar 

  43. Kumar P, Henikoff S, Ng PC . Predicting the effects of coding non-synonymous variants on protein function using the SIFT algorithm. Nat Protoc 2009; 4: 1073–1081.

    Article  CAS  PubMed  Google Scholar 

  44. Grolleau F, Gamelin L, Boisdron-Celle M, Lapied B, Pelhate M, Gamelin E . A possible explanation for a neurotoxic effect of the anticancer agent oxaliplatin on neuronal voltage-gated sodium channels. J Neurophysiol 2001; 85: 2293–2297.

    Article  CAS  PubMed  Google Scholar 

  45. Wu W, Zhang W, Qiao R, Chen D, Wang H, Wang Y et al. Association of XPD polymorphisms with severe toxicity in non-small cell lung cancer patients in a Chinese population. Clin Cancer Res 2009; 15: 3889–3895.

    Article  CAS  PubMed  Google Scholar 

  46. Yin J, Li J, Ma Y, Guo L, Wang H, Vogel U . The DNA repair gene ERCC2/XPD polymorphism Arg 156Arg (A22541C) and risk of lung cancer in a Chinese population. Cancer Lett 2005; 223: 219–226.

    Article  CAS  PubMed  Google Scholar 

  47. Furuta T, Ueda T, Aune G, Sarasin A, Kraemer KH, Pommier Y . Transcription-coupled nucleotide excision repair as a determinant of cisplatin sensitivity of human cells. Cancer Res 2002; 62: 4899–4902.

    CAS  PubMed  Google Scholar 

  48. Aloyz R, Xu ZY, Bello V, Bergeron J, Han FY, Yan Y et al. Regulation of cisplatin resistance and homologous recombinational repair by the TFIIH subunit XPD. Cancer Res 2002; 62: 5457–5462.

    CAS  PubMed  Google Scholar 

  49. Duldulao MP, Lee W, Nelson RA, Ho J, Le M, Chen Z et al. Gene polymorphisms predict toxicity to neoadjuvant therapy in patients with rectal cancer. Cancer 2013; 119: 1106–1112.

    Article  CAS  PubMed  Google Scholar 

  50. Wang Z, Xu B, Lin D, Tan W, Leaw S, Hong X et al. XRCC1 polymorphisms and severe toxicity in lung cancer patients treated with cisplatin-based chemotherapy in Chinese population. Lung Cancer 2008; 62: 99–104.

    Article  PubMed  Google Scholar 

  51. Han B, Gao G, Wu W, Gao Z, Zhao X, Li L et al. Association of ABCC2 polymorphisms with platinum-based chemotherapy response and severe toxicity in non-small cell lung cancer patients. Lung Cancer 2011; 72: 238–243.

    Article  PubMed  Google Scholar 

  52. Tournigand C, Andre T, Achille E, Lledo G, Flesh M, Mery-Mignard D et al. FOLFIRI followed by FOLFOX6 or the reverse sequence in advanced colorectal cancer: a randomized GERCOR study. J Clin Oncol 2004; 22: 229–237.

    Article  CAS  PubMed  Google Scholar 

  53. Cassidy J, Clarke S, az-Rubio E, Scheithauer W, Figer A, Wong R et al. Randomized phase III study of capecitabine plus oxaliplatin compared with fluorouracil/folinic acid plus oxaliplatin as first-line therapy for metastatic colorectal cancer. J Clin Oncol 2008; 26: 2006–2012.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

The NORDIC-VII study was supported by Merck-Serono, Darmstadt, Germany and Sanofi-Aventis, Oslo, Norway. The NORDIC-VII study is registered under trial number NCT00145314. This work was supported by the South-Eastern Norway Regional Health Authority, Holes Foundation, the Swedish Cancer Society, and the Gustav V Jubilee Clinic Foundation for Cancer Research, Sweden. The funding organizations did not influence the conduct of the study, data analysis and interpretation of the data or approval of the manuscript.

Author information

Author notes

  1. Y Wettergren and E H Kure: Shared last authorship.

Authors and Affiliations

  1. Department of Cancer Genetics, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway

    J B Kjersem, J Hamfjord & E H Kure

  2. Department of Oncology, Oslo University Hospital, Oslo, Norway

    M Thomsen, T Guren & K M Tveit

  3. Department of Surgery, Sahlgrenska Academy at University of Gothenburg, Sahlgrenska University Hospital/Östra, Gothenburg, Sweden

    G Carlsson, B Gustavsson & Y Wettergren

  4. Akershus University Hospital, Lørenskog, Norway

    T Ikdahl

  5. Department of Oncology, Ålesund Hospital, Møre and Romsdal Hospital Trust, Ålesund, Norway

    G Indrebø

  6. Department of Oncology, Odense University Hospital, Sdr Boulevard 29, Odense C, Denmark

    P Pfeiffer

  7. Department of Computer Science, University of Oslo, Oslo, Norway

    O Lingjærde

  8. Department of Cancer Genetics, K.G. Jebsen Center for Breast Cancer Research, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway

    O Lingjærde

Authors
  1. J B Kjersem
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. M Thomsen
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. T Guren
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. J Hamfjord
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. G Carlsson
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. B Gustavsson
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. T Ikdahl
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. G Indrebø
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. P Pfeiffer
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. O Lingjærde
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. K M Tveit
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Y Wettergren
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. E H Kure
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to E H Kure.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Additional information

Supplementary Information accompanies the paper on the The Pharmacogenomics Journal website

Supplementary information

PowerPoint slides

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Kjersem, J., Thomsen, M., Guren, T. et al. AGXT and ERCC2 polymorphisms are associated with clinical outcome in metastatic colorectal cancer patients treated with 5-FU/oxaliplatin. Pharmacogenomics J 16, 272–279 (2016). https://doi.org/10.1038/tpj.2015.54

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/tpj.2015.54

This article is cited by

Search

Advanced search

Quick links