Clinical and Genome-Wide Analysis of Cisplatin-Induced Peripheral Neuropathy in Survivors of Adult-Onset Cancer.
Clinical and Genome-Wide Analysis of Cisplatin-Induced Peripheral Neuropathy in Survivors of Adult-Onset Cancer.
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DOI：
10.1158/1078-0432.ccr-16-3224
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发表时间：
2017-10-01
期刊：
影响因子：
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通讯作者：
Platinum Study Group
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文献类型：
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作者：
Dolan ME;El Charif O;Wheeler HE;Gamazon ER;Ardeshir-Rouhani-Fard S;Monahan P;Feldman DR;Hamilton RJ;Vaughn DJ;Beard CJ;Fung C;Kim J;Fossa SD;Hertz DL;Mushiroda T;Kubo M;Einhorn LH;Cox NJ;Travis LB;Platinum Study Group
我们的目的是描述睾丸癌幸存者（TCS）中持续性顺铂诱导的周围神经病变（CisIPN）的临床影响、遗传风险因素和基因机制。接受顺铂治疗的TCS完成了经验证的EORTC QLQ-CIPN 20问卷。一个有序的CisIPN表型，并与年龄，吸烟，过量饮酒，高血压，体重指数，糖尿病，高胆固醇血症，累积顺铂剂量，和自我报告的健康进行了检查680 TCS。基因分型在Illumina HumanOmnitrile Exome芯片上进行。在质量控制和插补之后，680个遗传欧洲TCS中的510万个SNP形成了输入集。GWAS和PrediXcan分别用于鉴定遗传变异和遗传决定的基因表达性状，有助于CisIPN。我们评估了两个独立的数据集的复制：范德比尔特的电子健康数据库，BioVU和CALGB 90401试验。8个感觉项目构成的分量表具有良好的内部一致性（Cronbach α=0.88）。与CisIPN显著相关的变量包括诊断时的年龄（OR每年=1.06，p=2 × 10−9）、吸烟（OR=1.54，p=0.004）、过量饮酒（OR=1.83，p=0.007）和高血压（OR=1.61，p=0.03）。CisIPN与自我报告的健康状况较低（OR=0.56; p=2.6 × 10−9）和治疗后数年调整的体重增加相关（OR/Δkg/m2=1.05，p=0.004）。PrediXcan鉴定了MIDN和RPRD 1B的较低表达，以及与CisIPN相关的较高THEM 5表达（每个p值< 5 × 10−6），RPRD 1B的复制符合显著性标准（Fisher组合p=0.0089）。CisIPN与年龄、可改变的风险因素和RPRD 1B基因决定的表达水平相关。对相关基因的进一步研究可以阐明CisIPN的病理生理基础。
Our purpose was to characterize the clinical influences, genetic risk factors, and gene mechanisms contributing to persistent cisplatin-induced peripheral neuropathy (CisIPN) in testicular cancer survivors (TCS). TCS given cisplatin-based therapy completed the validated EORTC QLQ-CIPN20 questionnaire. An ordinal CisIPN phenotype was derived and associations with age, smoking, excess drinking, hypertension, body mass index, diabetes, hypercholesterolemia, cumulative cisplatin dose, and self-reported health were examined for 680 TCS. Genotyping was performed on the Illumina HumanOmniExpressExome chip. Following quality control and imputation, 5.1 million SNPs in 680 genetically European TCS formed the input set. GWAS and PrediXcan were used to identify genetic variation and genetically-determined gene expression traits, respectively, contributing to CisIPN. We evaluated two independent datasets for replication: Vanderbilt’s electronic health database, BioVU and CALGB 90401 trial. Eight sensory items formed a subscale with good internal consistency (Cronbach α=0.88). Variables significantly associated with CisIPN included age at diagnosis (OR per year=1.06, p=2 × 10−9), smoking (OR=1.54, p=0.004), excess drinking (OR=1.83, p=0.007), and hypertension (OR=1.61, p=0.03). CisIPN was correlated with lower self-reported health (OR=0.56; p=2.6 × 10−9) and weight gain adjusted for years since treatment (OR per Δkg/m2=1.05, p=0.004). PrediXcan identified lower expressions of MIDN and RPRD1B, and higher THEM5 expression as associated with CisIPN (p-value for each < 5 × 10−6) with replication of RPRD1B meeting significance criteria (Fisher’s combined p=0.0089). CisIPN is associated with age, modifiable risk factors and genetically-determined expression level of RPRD1B. Further study of implicated genes could elucidate the pathophysiologic underpinnings of CisIPN.