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Genetic variants in DNA repair genes as potential predictive markers for oxaliplatin chemotherapy in colorectal cancer

The Pharmacogenomics Journal volume 15, pages 505–512 (2015)Cite this article

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Abstract

Oxaliplatin-based chemotherapy exerts its effects through generating DNA damage. Hence, genetic variants in DNA repair pathways could modulate treatment response. We used a prospective cohort of 623 colorectal cancer patients with stage II–IV disease treated with adjuvant/palliative chemotherapy to comprehensively investigate 1727 genetic variants in the DNA repair pathways as potential predictive markers for oxaliplatin treatment. Single nucleotide polymorphisms (SNP) associations with overall survival and recurrence-free survival were assessed using a Cox regression model. Pathway analysis was performed using the gamma method. Patients carrying variant alleles of rs3783819 (MNAT1) and rs1043953 (XPC) experienced a longer overall survival after treatment with oxaliplatin than patients who did not carry the variant allele, while the opposite association was found in patients who were not treated with oxaliplatin (false discovery rate-adjusted P-values for heterogeneity 0.0047 and 0.0237, respectively). The nucleotide excision repair (NER) pathway was found to be most likely associated with overall survival in patients who received oxaliplatin (P-value=0.002). Our data show that genetic variants in the NER pathway are potentially predictive of treatment response to oxaliplatin.

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Acknowledgements

We thank all participants of the DACHS study, the interviewers, physicians and staff of the hospitals for their cooperation. Finally, the excellent technical assistance by the microarray unit of the German Cancer Research Center (especially Matthias Schick), Muhabbet Celik, Ursula Eilber, Sabine Behrens and Ute Handte-Daub was very much appreciated. We thank all those who contributed to the 1000 genomes project to make the imputation of additional SNPs possible. The DACHS study was supported by grants from the German Research Council (Deutsche Forschungsgemeinschaft, grant numbers BR 1704/6-1, BR 1704/6-3, BR 1704/6-4 and CH 390 117/1-1) and the German Federal Ministry of Education and Research (grant numbers 01ER0814 and 01ER0815). GECCO is supported by the National Cancer Institute, National Institutes of Health, US Department of Health and Human Services, grant numbers U01 CA137088; R01 CA059045.

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Authors and Affiliations

  1. Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany

    E J Kap, P Seibold, S Richter & J Chang-Claude

  2. Division of Preventive Oncology, National Center for Tumor Diseases (NCT) and DKFZ, Heidelberg, Germany

    D Scherer, N Habermann, Y Balavarca & C M Ulrich

  3. Division of Clinical Epidemiology and Aging Research, DKFZ, Heidelberg, Germany

    L Jansen, M Hoffmeister & H Brenner

  4. Division of Biostatistics, DKFZ, Heidelberg, Germany

    N Becker & A Benner

  5. Division of Molecular Epidemiology, DKFZ, Heidelberg, Germany

    K Pfütze & B Burwinkel

  6. Division Molecular Biology of Breast Cancer, Department of Gynecology and Obstetrics, University of Heidelberg, Heidelberg, Germany

    K Pfütze & B Burwinkel

  7. Division of Epigenomics and Cancer Risk Factors, DKFZ, Heidelberg, Germany

    O Popanda

  8. Department of General, Visceral and Transplantation Surgery, University Hospital Heidelberg, University of Heidelberg, Heidelberg, Germany

    A Ulrich

  9. Cancer Prevention Program, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA

    C M Ulrich

  10. German Cancer Consortium (DKTK), Heidelberg, Germany

    H Brenner

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Correspondence to J Chang-Claude.

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Kap, E., Seibold, P., Richter, S. et al. Genetic variants in DNA repair genes as potential predictive markers for oxaliplatin chemotherapy in colorectal cancer. Pharmacogenomics J 15, 505–512 (2015). https://doi.org/10.1038/tpj.2015.8

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