Association of the Charcot-Marie-Tooth disease gene ARHGEF10 with paclitaxel induced peripheral neuropathy in NCCTG N08CA (Alliance).
Association of the Charcot-Marie-Tooth disease gene ARHGEF10 with paclitaxel induced peripheral neuropathy in NCCTG N08CA (Alliance).
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DOI：
10.1016/j.jns.2015.06.056
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发表时间：
2015-10-15
影响因子：
4.4
通讯作者：
Beutler AS
中科院分区：
文献类型：
--
作者：
Boora GK;Kulkarni AA;Kanwar R;Beyerlein P;Qin R;Banck MS;Ruddy KJ;Pleticha J;Lynch CA;Behrens RJ;Züchner S;Loprinzi CL;Beutler AS
患者对毒性暴露的反应中发生多发性神经病的易感性可能具有遗传基础。先前的研究Alliance N 08 C1发现Charcot-Marie-Tooth病（CMT）基因ARHGEF 10与紫杉醇化疗诱导的周围神经病变（CIPN）相关，与三种非同义的复发性单核苷酸变异（SNV）有关，其中rs 9657362的作用最强，rs 2294039和rs 17683288的作用很弱。在本报告中，选择Alliance N 08 CA尝试复制上述结果。选择N 08 CA是因为它是迄今为止在CIPN领域进行的方法学上最相似的研究（与N 08 C1）。N 08 CA入组了接受神经毒性化疗药物紫杉醇的患者。多发性神经病通过连续重复给予先前验证的患者报告结果工具CIPN 20进行评估。在研究范围内，使用Rasch型模型在n=138名合格患者中进行极端表型分型，从中选择“病例”和“对照”用于通过TaqMan PCR进行的SNV遗传分析。在预先规定的主要终点下，发现ARHGEF 10与CIPN显著相关，显著性水平为p=0.024。与原始研究一样，rs 9657362与单一SNV的关联最强（比值比=3.56，p=0.018）。为了进一步比较新研究和先前研究的结果，测试了统计学“分类器”，N 08 CA的ROC曲线下面积为0.60，N 08 C1的ROC曲线下面积为0.66，证明了良好的一致性。在复制研究N 08 CA中对N 08 C1的主要终点进行了重新检验，验证了ARHGEF 10与CIPN的相关性。
The predisposition of patients to develop polyneuropathy in response to toxic exposure may have a genetic basis. The previous study Alliance N08C1 found an association of the Charcot-Marie-Tooth disease (CMT) gene ARHGEF10 with paclitaxel chemotherapy induced peripheral neuropathy (CIPN) related to the three non-synonymous, recurrent single nucleotide variants (SNV), whereby rs9657362 had the strongest effect, and rs2294039 and rs17683288 contributed only weakly. In the present report, Alliance N08CA was chosen to attempt to replicate the above finding. N08CA was chosen because it is the methodologically most similar study (to N08C1) performed in the CIPN field to date. N08CA enrolled patients receiving the neurotoxic chemotherapy agent paclitaxel. Polyneuropathy was assessed by serial repeat administration of the previously validated patient reported outcome instrument CIPN20. A study wide, Rasch type model was used to perform extreme phenotyping in n=138 eligible patients from which “cases” and “controls” were selected for genetic analysis of SNV performed by TaqMan PCR. A significant association of ARHGEF10 with CIPN was found under the pre-specified primary endpoint, with a significance level of p=0.024. As in the original study, the strongest association of a single SNV was seen for rs9657362 (odds ratio=3.56, p=0.018). To further compare results across the new and the previous study, a statistical “classifier” was tested, which achieved a ROC area under the curve of 0.60 for N08CA and 0.66 for N08C1, demonstrating good agreement. Retesting of the primary endpoint of N08C1 in the replication study N08CA validated the association of ARHGEF10 with CIPN.