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

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