顺铂所致耳鸣的临床与全基因组分析揭示新的耳毒性机制
Clinical and Genome-wide Analysis of Cisplatin-induced Tinnitus Implicates Novel Ototoxic Mechanisms.
作者信息
El Charif Omar, Mapes Brandon, Trendowski Matthew R, Wheeler Heather E, Wing Claudia, Dinh Paul C, Frisina Robert D, Feldman Darren R, Hamilton Robert J, Vaughn David J, Fung Chunkit, Kollmannsberger Christian, Mushiroda Taisei, Kubo Michiaki, Gamazon Eric R, Cox Nancy J, Huddart Robert, Ardeshir-Rouhani-Fard Shirin, Monahan Patrick, Fossa Sophie D, Einhorn Lawrence H, Travis Lois B, Dolan M Eileen
机构信息
Department of Medicine, University of Chicago, Chicago, Illinois.
Departments of Biology and Computer Science, Loyola University Chicago, Chicago, Illinois.
出版信息
Clin Cancer Res. 2019 Jul 1;25(13):4104-4116. doi: 10.1158/1078-0432.CCR-18-3179. Epub 2019 Apr 5.
PURPOSE
Cisplatin, a commonly used chemotherapeutic, results in tinnitus, the phantom perception of sound. Our purpose was to identify the clinical and genetic determinants of tinnitus among testicular cancer survivors (TCS) following cisplatin-based chemotherapy.
EXPERIMENTAL DESIGN
TCS ( = 762) were dichotomized to cases (moderate/severe tinnitus; = 154) and controls (none; = 608). Logistic regression was used to evaluate associations with comorbidities and SNP dosages in genome-wide association study (GWAS) following quality control and imputation (covariates: age, noise exposure, cisplatin dose, genetic principal components). Pathway over-representation tests and functional studies in mouse auditory cells were performed.
RESULTS
Cisplatin-induced tinnitus (CisIT) significantly associated with age at diagnosis ( = 0.007) and cumulative cisplatin dose ( = 0.007). CisIT prevalence was not significantly greater in 400 mg/m-treated TCS compared with 300 ( = 0.41), but doses >400 mg/m (median 580, range 402-828) increased risk by 2.61-fold ( < 0.0001). CisIT cases had worse hearing at each frequency (0.25-12 kHz, < 0.0001), and reported more vertigo (OR = 6.47; < 0.0001) and problems hearing in a crowd (OR = 8.22; < 0.0001) than controls. Cases reported poorer health ( < 0.0001) and greater psychotropic medication use (OR = 2.4; = 0.003). GWAS suggested a variant near (rs7606353, = 2 × 10) and eQTLs were significantly enriched independently of that SNP ( = 0.018). overexpression in HEI-OC1, a mouse auditory cell line, resulted in resistance to cisplatin-induced cytotoxicity. Pathway analysis implicated potassium ion transport (q = 0.007).
CONCLUSIONS
CisIT associated with several neuro-otological symptoms, increased use of psychotropic medication, and poorer health. , expressed in the cochlear lateral wall, was implicated as protective. Future studies should investigate otoprotective targets in supporting cochlear cells.
目的
顺铂是一种常用的化疗药物，会导致耳鸣，即声音的幻听。我们的目的是确定基于顺铂化疗的睾丸癌幸存者（TCS）中耳鸣的临床和遗传决定因素。
实验设计
将TCS（n = 762）分为病例组（中度/重度耳鸣；n = 154）和对照组（无耳鸣；n = 608）。在进行质量控制和归因后，使用逻辑回归评估与合并症和全基因组关联研究（GWAS）中SNP剂量的关联（协变量：年龄、噪声暴露、顺铂剂量、遗传主成分）。对小鼠听觉细胞进行了通路过度表达测试和功能研究。
结果
顺铂诱导的耳鸣（CisIT）与诊断时的年龄（P = 0.007）和累积顺铂剂量（P = 0.007）显著相关。与接受300mg/m²治疗的TCS相比，接受400mg/m²治疗的TCS中CisIT患病率无显著更高（P = 0.41），但剂量>400mg/m²（中位数580，范围402 - 828）使风险增加2.61倍（P < 0.0001）。CisIT病例在每个频率（0.25 - 12kHz，P < 0.0001）的听力都更差，并且与对照组相比，报告有更多眩晕（OR = 6.47；P < 0.0001）和在人群中听力问题（OR = 8.22；P < 0.0001）。病例组报告健康状况较差（P < 0.0001）且精神药物使用更多（OR = 2.4；P = 0.003）。GWAS表明靠近某个基因（rs7606353，P = 2×10⁻⁸）的一个变异，并且独立于该SNP，eQTLs显著富集（P = 0.018）。在小鼠听觉细胞系HEI - OC1中该基因的过表达导致对顺铂诱导的细胞毒性具有抗性。通路分析涉及钾离子转运（q = 0.007）。
结论
CisIT与几种神经耳科症状、精神药物使用增加和健康状况较差相关。在耳蜗外侧壁表达的某个基因被认为具有保护作用。未来的研究应调查支持耳蜗细胞的耳保护靶点。
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