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全外显子组测序显示预测紫杉醇剂量限制性神经病的CYP3A4变异缺陷

Whole-exome sequencing reveals defective CYP3A4variants predictive for paclitaxel dose-limiting neuropathy
课程网址: http://videolectures.net/mdo2014_apellaniz_ruiz_neuropathy/  
主讲教师: María Apellániz Ruiz
开课单位: 西班牙国家癌症研究中心
开课时间: 2014-07-21
课程语种: 英语
中文简介:
问题 紫杉醇是一种广泛使用的化疗药物，可导致严重的周围神经病变，导致剂量减少和治疗中止，如果长期使用，会降低患者的生活质量。改变紫杉醇药代动力学的遗传变异被认为会增加神经病变的风险，但导致个体间紫杉醇毒性易感性差异的主要原因尚不清楚。在这项研究中，我们使用全外显子组测序（WES）来确定与紫杉醇诱导的神经病变相关的遗传变异，并使用独立队列证实了我们的结果。 方法 选择8例严重紫杉醇诱导的周围神经病变患者进行WES。采用dHPLC对228名癌症患者进行变异筛查，并进行关联分析，这些患者具有关于紫杉醇神经病的完整数据。 后果 WES发现两名患者具有罕见的CYP3A4变异：一个罕见的过早终止密码子（CYP3A4*20等位基因）和一个新的错义变异（c.1165C>T，p.P389S，命名为CYP3A4*25）。在独立系列中对CYP3A4变异体进行筛查，发现另外三个CYP3A4*20携带者和其他变异体。所有具有CYP3A4*20等位基因的患者均患有紫杉醇诱导的3级神经病变。与野生型CYP3A4患者相比，这些患者发生紫杉醇诱发神经病变的风险增加2倍（P=0.042），紫杉醇治疗修改的概率增加7倍（P=0.0058）。 结论 CYP3A4缺陷变异体导致紫杉醇剂量限制性神经病的高风险，因此，为紫杉醇治疗个体化提供了基础。
课程简介: Questions Paclitaxel, a widely-used chemotherapeutic drug, can cause severe peripheral neuropathy, causing dose reductions and treatment suspensions and, when long-lasting, a decrease in the quality of life of patients. Genetic variants altering paclitaxel pharmacokinetics have been proposed to increase the risk for neuropathy, but the major causes of inter-individual differences in susceptibility to paclitaxel toxicity remain unexplained. In this study we used whole-exome sequencing (WES) to identify genetic variants associated with paclitaxel-induced neuropathy and confirmed our results using an independent cohort. Methods Eight patients with severe paclitaxel-induced peripheral neuropathy were selected for WES. An independent cohort of 228 cancer patients with complete data regarding paclitaxel neuropathy was used for variant screening by dHPLC and association analysis. Results WES revealed two patients with rare CYP3A4 variants: a rare premature stop codon (CYP3A4*20 allele) and a novel missense variant (c.1165C>T, p.P389S, named CYP3A4*25). Screening for CYP3A4 variants in the independent series revealed three more CYP3A4*20 carriers and additional variants. All patients with CYP3A4*20 allele had a grade 3 paclitaxel-induced neuropathy. These patients had 2-fold increased risk of paclitaxel-induced neuropathy (P=0.042) and 7-fold higher probability of paclitaxel treatment modifications (P=0.0058) than patients with wild-type CYP3A4. Conclusions CYP3A4 defective variants confer high risk of paclitaxel dose-limiting neuropathy, thus, providing a basis for paclitaxel treatment individualization.
关 键 词: 紫杉醇; 全外显子组测序; 遗传变异
课程来源: 视频讲座网
数据采集: 2021-12-26：zkj
最后编审: 2021-12-26：zkj
阅读次数: 53

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