Validation of Genetic Markers Associated with Survival in Colorectal Cancer Patients Treated with Oxaliplatin-Based Chemotherapy

Abstract

Background: Associations between candidate genetic variants Results: Twelve SNPs were predictive and/or prognostic at and treatment outcomes of oxaliplatin, a drug commonly used for P < 0.05 with differential survival based on the type of treatment, colorectal cancer patients, have been reported but not robustly in patients with stage II–III (GSTM5-rs11807, ERCC2-rs13181, established. This study aimed to validate previously reported progERCC2-rs1799793, ERCC5-rs2016073, XPC-rs2228000, P2RX7-nostic and predictive genetic markers for oxaliplatin treatment rs208294, HMGB1-rs1360485) and in patients with stage IV outcomes and evaluate additional putative functional variants. (GSTM5-rs11807, MNAT1-rs3783819, MNAT1-rs4151330, CXCR1-Methods: Fifty-three SNPs were selected based on previous rs2234671, VEGFA-rs833061, P2RX7-rs2234671). In addition, five reports (40 SNPs) or putative function in candidate genes (13 novel putative functional SNPs were identified to be predictive SNPs). We used data from 1,502 patients with stage II–IV colorectal (ATP8B3-rs7250872, P2RX7-rs2230911, RPA1-rs5030755, MGMT-cancer who received primary adjuvant chemotherapy, 37% of whom rs12917, P2RX7-rs2227963). received oxaliplatin treatment. Multivariable Cox proportional Conclusions: Some SNPs yielded prognostic and/or predictive hazards models for overall survival and progression-free survival associations significant at P < 0.05, however, none of the associawere applied separately in stage II–III and stage IV patients. For tions remained significant after correction for multiple testing. predictive SNPs, differential outcomes according to the type of Impact: We did not robustly confirm previously reported chemotherapy (oxaliplatin-based vs. others) were evaluated using SNPs despite some suggestive findings but identified further potenan interaction term. For prognostic SNPs, the association was tial predictive SNPs, which warrant further investigation in well-assessed solely in patients with oxaliplatin-based treatment. powered studies.