Association of Voltage-Gated Sodium Channel Genetic Polymorphisms with Oxaliplatin-Induced Chronic Peripheral Neuropathy in South Indian Cancer Patients

Oxaliplatin is a platinum drug active against digestive tract cancers. Among its side effects, peripheral neuropathy is one of the dose-limiting toxicities. This affects around 50 to 70% of patients but the pathophysiology of development of oxaliplatin-induced peripheral neuropathy (OXAIPN) remains unclear. Sodium channels (SCNAs) play major role in neuronal electrical signaling processes and mutations in SCNAs lead to various neuronal diseases involving the central and peripheral nervous systems. In this study, we evaluated whether SCNA genetic variants might be associated with risk of chronic OXAIPN in patients with digestive tract cancers treated with oxaliplatin. METHODOLOGY: Blood samples from 228 digestive tract cancer patients who had received oxaliplatin in adjuvant and neoadjuvant or metastatic settings were obtained and genomic DNA was extracted by phenol-chloroform extraction. Genotyping was performed with the real-time polymerase chain reaction (RT-PCR) using validated real-time TaqMan single nucleotide polymorphism (SNP) genotyping assays. Neuropathy was evaluated and graded according to National Cancer Institute Common Toxicity Criteria (NCI-CTC) version 4.03. RESULTS: We found that the rs6746030 polymorphic variant of SCN9A was significantly associated with a higher incidence of chronic OXAIPN (GA+AA vs GG: OR=1.8, 95% CI=1.04-3.4, P=0.04; dominant model) while the rs6754031 variant was linked with a lower incidence (OR=0.45, 95% CI=0.22-0.77, P=0.005; dominant model). The SCN 10A polymorphic variant was associated with severity of chronic OXAIPN (P=0.006, OR=2.0, 95% CI=1.2 - 3.3). CONCLUSION: The results of the present prospective study provide evidence in support of a causal relationship between chronic OXAIPN and voltage gated sodium channel polymorphisms. However, further studies from independent groups are required to validate these results.