SCN9A基因多态性与奥沙利铂所致神经病变相关。
Genetic polymorphisms of SCN9A are associated with oxaliplatin-induced neuropathy.
作者信息
Sereno María, Gutiérrez-Gutiérrez Gerardo, Rubio Juan Moreno, Apellániz-Ruiz María, Sánchez-Barroso Lara, Casado Enrique, Falagan Sandra, López-Gómez Miriam, Merino María, Gómez-Raposo César, Rodriguez-Salas Nuria, Tébar Francisco Zambrana, Rodríguez-Antona Cristina
机构信息
Medical Oncology Department, Infanta Sofía University Hospital, SS de los Reyes, Madrid, Spain.
Neurology Department, Infanta Sofía University Hospital, SS de los Reyes, Madrid, Spain.
出版信息
BMC Cancer. 2017 Jan 19;17(1):63. doi: 10.1186/s12885-016-3031-5.
BACKGROUND
Oxaliplatin 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.
METHODS
Blood 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.
RESULTS
We 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.
背景
奥沙利铂是一种对消化肿瘤有效的化疗药物。周围神经病变是该药物最重要的剂量限制性毒性之一。约60 - 80%的患者会出现这种情况，其中15%会发展为严重神经病变。奥沙利铂神经毒性的病理生理学仍不清楚。SCN9A是一个编码钠通道亚型（IX型，α亚基）的基因，该基因的突变与神经性感觉有关。在本研究中，我们调查了SCN9A基因变异是否与接受奥沙利铂治疗的癌症患者发生神经毒性的风险相关。
方法
从马德里的三家医院获取了94例诊断为消化道癌症并在辅助或转移情况下接受过奥沙利铂治疗的患者的血样。这些患者被分为两组：“病例组”出现奥沙利铂诱导的3 - 4级神经病变（n = 48），“对照组”（n = 46）无神经病变或为1级。由一名神经科专家对神经病变进行评估，包括临床检查，并根据经过验证的神经学量表进行分类：美国国立癌症研究所通用毒性标准（NCI - CTC）、奥沙利铂特异性神经毒性量表（OSNS）和总神经病变评分（TNS）。对3个SCN9A错义多态性进行基因分型：rs6746030（R1150W）、rs74401238（R1110Q）和rs41268673（P610T），并评估基因型与神经病变之间的关联。
结果
我们发现SCN9A rs6746030与严重神经病变的保护作用相关（OR = 0.39，95%CI = 0.16 - 0.96；p = 0.041）。对糖尿病进行校正的多变量分析提供了类似的结果（p = 0.036）。未检测到rs74401238和rs41268673在神经病变风险方面的显著差异。
结论
SCN9A rs6746030与严重奥沙利铂诱导的周围神经病变的保护作用相关。这项探索性研究的验证正在一个独立队列中进行。
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