title: Genetic variants in DNA repair genes as potential predictive markers for oxaliplatin chemotherapy in colorectal cancer.
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.
authors.affiliation: Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: E J
authors.initials: EJ
authors.lastname: Kap
authors.affiliation: Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: P
authors.initials: P
authors.lastname: Seibold
authors.affiliation: Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Richter
authors.affiliation: Division of Preventive Oncology, National Center for Tumor Diseases (NCT) and DKFZ, Heidelberg, Germany.
authors.forename: D
authors.initials: D
authors.lastname: Scherer
authors.affiliation: Division of Preventive Oncology, National Center for Tumor Diseases (NCT) and DKFZ, Heidelberg, Germany.
authors.forename: N
authors.initials: N
authors.lastname: Habermann
authors.affiliation: Division of Preventive Oncology, National Center for Tumor Diseases (NCT) and DKFZ, Heidelberg, Germany.
authors.forename: Y
authors.initials: Y
authors.lastname: Balavarca
authors.affiliation: Division of Clinical Epidemiology and Aging Research, DKFZ, Heidelberg, Germany.
authors.forename: L
authors.initials: L
authors.lastname: Jansen
authors.affiliation: Division of Biostatistics, DKFZ, Heidelberg, Germany.
authors.forename: N
authors.initials: N
authors.lastname: Becker
authors.affiliation: Division of Molecular Epidemiology, DKFZ, Heidelberg, Germany.|Division Molecular Biology of Breast Cancer, Department of Gynecology and Obstetrics, University of Heidelberg, Heidelberg, Germany.
authors.forename: K
authors.initials: K
authors.lastname: Pfütze
authors.affiliation: Division of Epigenomics and Cancer Risk Factors, DKFZ, Heidelberg, Germany.
authors.forename: O
authors.initials: O
authors.lastname: Popanda
authors.affiliation: Division of Clinical Epidemiology and Aging Research, DKFZ, Heidelberg, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Hoffmeister
authors.affiliation: Department of General, Visceral and Transplantation Surgery, University Hospital Heidelberg, University of Heidelberg, Heidelberg, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Ulrich
authors.affiliation: Division of Biostatistics, DKFZ, Heidelberg, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Benner
authors.affiliation: Division of Preventive Oncology, National Center for Tumor Diseases (NCT) and DKFZ, Heidelberg, Germany.|Cancer Prevention Program, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.
authors.forename: C M
authors.initials: CM
authors.lastname: Ulrich
authors.affiliation: Division of Molecular Epidemiology, DKFZ, Heidelberg, Germany.|Division Molecular Biology of Breast Cancer, Department of Gynecology and Obstetrics, University of Heidelberg, Heidelberg, Germany.
authors.forename: B
authors.initials: B
authors.lastname: Burwinkel
authors.affiliation: Division of Clinical Epidemiology and Aging Research, DKFZ, Heidelberg, Germany.|German Cancer Consortium (DKTK), Heidelberg, Germany.
authors.forename: H
authors.initials: H
authors.lastname: Brenner
authors.affiliation: Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: J
authors.initials: J
authors.lastname: Chang-Claude
mesh_terms: D000368:Aged; D000483:Alleles; D014408:Biomarkers, Tumor / Q000235:genetics*; D016022:Case-Control Studies; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000235:genetics*; D004260:DNA Repair / Q000187:drug effects* / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics; D005260:Female; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D009944:Organoplatinum Compounds / Q000627:therapeutic use*; D000077150:Oxaliplatin; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011446:Prospective Studies
chemical_list: D014408:Biomarkers, Tumor; D004268:DNA-Binding Proteins; D009944:Organoplatinum Compounds; D000077150:Oxaliplatin