Genetic polymorphisms of SCN9A are associated with oxaliplatin-induced neuropathy

Abstract

BackgroundOxaliplatin is a chemotherapy agent active against digestive tumors. Peripheral neuropathy is one of the most important dose-limiting toxicity of this drug. It occurs in around 60–80% of the patients, and 15% of them develop severe neuropathy. The pathophysiology of oxaliplatin neurotoxicity remains unclear. SCN9A is a gene codifying for a subtype sodium channel (type IX, subunit α) and mutations in this gene are involved in neuropathic perception. In this study we investigated whether SCN9A genetic variants were associated with risk of neurotoxicity in patients diagnosed of cancer on treatment with oxaliplatin.MethodsBlood samples from 94 patients diagnosed of digestive cancer that had received oxaliplatin in adjuvant or metastatic setting were obtained from three hospitals in Madrid. These patients were classified into two groups: “cases” developed oxaliplatin-induced grade 3–4 neuropathy (n = 48), and “controls” (n = 46) had no neuropathy or grade 1. The neuropathy was evaluated by an expert neurologist and included a clinical examination and classification according to validated neurological scales: National Cancer Institute Common Toxicity Criteria (NCI-CTC), Oxaliplatin-Specific Neurotoxicity Scale (OSNS) and Total Neuropathy score (TNS). Genotyping was performed for 3 SCN9A missense polymorphisms: rs6746030 (R1150W), rs74401238 (R1110Q) and rs41268673 (P610T), and associations between genotypes and neuropathy were evaluated.ResultsWe found that SCN9A rs6746030 was associated with protection for severe neuropathy (OR = 0.39, 95% CI = 0.16–0.96; p = 0.041). Multivariate analysis adjusting for diabetes provided similar results (p = 0.036). No significant differences in neuropathy risk were detected for rs74401238 and rs41268673.Conclusion SCN9A rs6746030 was associated with protection for severe oxaliplatin-induced peripheral neuropathy. The validation of this exploratory study is ongoing in an independent series.

A Prospective Study of Chronic Oxaliplatin-Induced Neuropathy in Patients with Colon Cancer: Long-Term Outcomes and Predictors of Severe Oxaliplatin-Induced Neuropathy

“… 24 Recent pharmacogenetic studies have investigated target genes in the oxaliplatin metabolism, detoxification, or excretion pathways to predict severe OIPN. 27 28 29 The present study identified reductions of the a-SAP of >11.5% in the median nerve between baseline and four cycles ( p =0.031) and of >22.5% in the sural nerve between four and eight cycles ( p =0.031) as early predictors of the development of severe OIPN at the end of treatment. These findings are similar to a >30% decrease in the a-SAP from the baseline value in the radial and dorsal sural nerves mid-treatment being associated with severe OIPN at the end of treatment.…”

Taxane-induced sensory peripheral neuropathy is associated with an SCN9A single nucleotide polymorphism in Japanese patients

“…A recent study suggested that SNPs in voltage-gated sodium channel genes (SCN9A-rs6754031 and SCN10A-rs12632942) can cause oxaliplatin-based peripheral neurotoxicity [24,25,33,34]. A polymorphism in SCN9A (rs6746030) was also reported to be associated with decreased neurotoxicity [35]. However, these polymorphisms were not associated with TIPN in our study.…”

Chemotherapy-induced peripheral neuropathy—part 2: focus on the prevention of oxaliplatin-induced neurotoxicity

“…The development of acute oxaliplatin-induced peripheral neuropathy was altered in patients with single-nucleotide polymorphisms in SCNA genes encoding selected Na v channels. A polymorphism (rs2302237) in the SCN4A gene, which encodes the Na v 1.4 channel and a polymorphism (rs1263292) in the SCN10A coding for Na v 1.8 channel have been associated with an increased incidence of acute oxaliplatin-induced CIPN [27], while a polymorphism (rs6746030) in the SCN9A gene, which encodes the Na v 1.7 channel, protected against severe oxaliplatin-induced CIPN [28].…”