Genetic polymorphisms of SCN9A are associated with oxaliplatin-induced neuropathy

María Sereno,Cristina Rodríguez-Antona,María Apellániz-Ruiz,Lara Sánchez-Barroso,Sandra Falagan,María Merino,Nuria Rodriguez-Salas,Miriam López-Gómez,Juan Moreno Rubio,Gerardo Gutiérrez-Gutiérrez,Francisco Zambrana Tébar,César Gómez-Raposo,Enrique Casado

doi:10.1186/s12885-016-3031-5

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.ConclusionSCN9A rs6746030 was associated with protection for severe oxaliplatin-induced peripheral neuropathy. The validation of this exploratory study is ongoing in an independent series.

Highlights

Oxaliplatin is a chemotherapy agent active against digestive tumors
The severity of the acute oxaliplatin-induced neuropathy (OXLIN) was evaluated before every cycle and chronic or persistent toxicity was evaluated up to 3 months after last chemotherapy cycle
These findings suggest that SCN9A rs6746030 (p.R1150W) variant allele protects against the development of moderate-severe OXLIN (Table 2)

Summary

Introduction

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. In this study we investigated whether SCN9A genetic variants were associated with risk of neurotoxicity in patients diagnosed of cancer on treatment with oxaliplatin. Oxaliplatin is a subtype of platinum drugs with significant activity against advanced or metastatic digestive tumors, mainly colorectal cancer (CRC) [1]. Peripheral neuropathy (PN) is a dose-limiting toxicity of oxaliplatin and classically induces two recognized forms of PN: acute and chronic [2]. Whereas acute PN is not dose-dependent, cumulative doses of oxaliplatin are related to occurrence of chronic peripheral neuropathy [3].

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Conclusion