Voltage-Gated Sodium Channel Polymorphisms Play a Pivotal Role in the Development of Oxaliplatin-Induced Peripheral Neurotoxicity Results From a Prospective Multicenter Study
Voltage-Gated Sodium Channel Polymorphisms Play a Pivotal Role in the Development of Oxaliplatin-Induced Peripheral Neurotoxicity Results From a Prospective Multicenter Study
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DOI：
10.1002/cncr.28234
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发表时间：
2013-10-01
期刊：
影响因子：
6.2
通讯作者：
Kalofonos, Haralabos P.
中科院分区：
文献类型：
--
作者：
Argyriou, Andreas A.;Cavaletti, Guido;Kalofonos, Haralabos P.
背景：目前的前瞻性多中心研究试图确定电压门控钠通道(SCNAs)基因的单核苷酸多态性可能使接受亚叶酸钙、5-氟尿嘧啶和奥沙利铂(FOLFOX)或奥沙利铂加卡培他滨(XELOX)治疗结直肠癌(CRC)的患者发生奥沙利铂诱导的周围神经病(OXAIPN)的发生率和严重程度增加。方法采用实时聚合酶链式反应(RT-PCR)对200例结直肠癌患者进行基因分型。所有患者都接受了以奥沙利铂为基础的化疗，无论是在辅助环境中还是在转移环境中。使用临床版神经病变总评分和神经感觉国家癌症研究所共同毒性标准(版本3.0)对累积OXAIPN的发生率和严重程度进行分级。在每次临床评估时，使用描述性问卷(是/否回答格式)评估急性OXAIPN的发生率。在调整混杂因素的Logistic回归分析中，两个单核苷酸多态(即SCN4A-rs2302237和SCN10A-rs1263292)与急性OXAIPN的发病率显著相关(rs2302237：优势比2.62[95%可信区间(95%CI)，1.15-6.00]；P=.019；和rs12632942：OR为0.39[95%CI，0.17~0.88]；P=.023。然而，只有SCN4A-rs2302237对急性OXAIPN的临床严重程度(OR，2.50[95%CI，1.35-4.63]；P=.0029)和累积性/慢性OXAIPN的发生(OR，2.47[95%CI，1.04-5.85]；P=.037)也有预测作用。然而，来自独立研究小组的进一步研究有理由证实这些结果。癌症2013；119：3570-3577.(C)2013美国癌症学会。据作者所知，到目前为止还没有确定可靠的遗传或分子生物标记物来检测高危患者患奥沙利铂诱导的周围神经病变(OXAIPN)。目前的研究结果支持电压门控钠通道(SCNA)基因多态与OXAIPN之间的因果关系。
BACKGROUNDThe current prospective, multicenter study sought to identify single nucleotide polymorphisms of voltage-gated sodium channels (SCNAs) genes that might confer susceptibility to an increased incidence and severity of oxaliplatin-induced peripheral neuropathy (OXAIPN) in patients treated with either leucovorin, 5-fluorouracil, and oxaliplatin (FOLFOX) or oxaliplatin plus capecitabine (XELOX) for colorectal cancer (CRC).METHODSA total of 200 patients with CRC were genotyped with real-time polymerase chain reaction using locked nucleic acid hydrolysis probes or allele-specific primers. All patients had received oxaliplatin-based chemotherapy, either in the adjuvant or metastatic setting. The incidence and severity of cumulative OXAIPN was graded using the clinical version of the Total Neuropathy Score and the neurosensory National Cancer Institute Common Toxicity Criteria (version 3.0). The incidence of acute OXAIPN was assessed using a descriptive questionnaire (yes/no response format) at each clinical evaluation. Acute OXAIPN was present in 169 of 200 patients (84.5%), whereas after treatment discontinuation, the cumulative/chronic form of neurotoxicity occurred in 145 of 200 patients (72.5%).RESULTSIn the logistic regression analysis adjusted for confounding factors, the overdominant model (CT vs CC+TT) of 2 single nucleotide polymorphisms (ie, SCN4A-rs2302237 and SCN10A-rs1263292) emerged as being significantly associated with an increased incidence of acute OXAIPN (rs2302237: odds ratio of 2.62 [95% confidence interval (95% CI), 1.15-6.00]; P=.019; and rs12632942: OR of 0.39 [95% CI, 0.17-0.88]; P=.023). However, only SCN4A-rs2302237 emerged as also being predictive of the clinical severity of acute OXAIPN (OR, 2.50 [95% CI, 1.35-4.63]; P=.0029) and the occurrence of cumulative/chronic OXAIPN (OR, 2.47 [95% CI, 1.04-5.85]; P=.037).CONCLUSIONSThe results of the current study provide evidence to support a causal relationship between SCNA polymorphisms and OXAIPN. However, further studies from independent groups are warranted to confirm these results. Cancer 2013;119:3570-3577.. (c) 2013 American Cancer Society.To the authors' knowledge, no reliable genetic or molecular biomarkers have been identified to date to detect patients at high risk of developing oxaliplatin-induced peripheral neuropathy (OXAIPN). The results of the current study provide evidence to support a causal relationship between voltage-gated sodium channel (SCNA) polymorphisms and OXAIPN.