Department of Medicine, University of Chicago, Chicago, Illinois, USA.
Division of Medical Oncology, Indiana University, Indianapolis, Indiana, USA.
Cancer Med. 2022 Jul;11(14):2801-2816. doi: 10.1002/cam4.4644. Epub 2022 Mar 23.
Cisplatin is a critical component of first-line chemotherapy for several cancers, but causes peripheral sensory neuropathy, hearing loss, and tinnitus. We aimed to identify comorbidities for cisplatin-induced neurotoxicities among large numbers of similarly treated patients without the confounding effect of cranial radiotherapy.
Utilizing linear and logistic regression analyses on 1680 well-characterized cisplatin-treated testicular cancer survivors, we analyzed associations of hearing loss, tinnitus, and peripheral neuropathy with nongenetic comorbidities. Genome-wide association studies and gene-based analyses were performed on each phenotype.
Hearing loss, tinnitus, and peripheral neuropathy, accounting for age and cisplatin dose, were interdependent. Survivors with these neurotoxicities experienced more hypertension and poorer self-reported health. In addition, hearing loss was positively associated with BMIs at clinical evaluation and nonwork-related noise exposure (>5 h/week). Tinnitus was positively associated with tobacco use, hypercholesterolemia, and noise exposure. We observed positive associations between peripheral neuropathy and persistent vertigo, tobacco use, and excess alcohol consumption. Hearing loss and TXNRD1, which plays a key role in redox regulation, showed borderline significance (p = 4.2 × 10 ) in gene-based analysis. rs62283056 in WFS1 previously found to be significantly associated with hearing loss (n = 511), was marginally significant in an independent replication cohort (p = 0.06; n = 606). Gene-based analyses identified significant associations between tinnitus and WNT8A (p = 2.5 × 10 ), encoding a signaling protein important in germ cell tumors.
Genetics variants in TXNRD1 and WNT8A are notable risk factors for hearing loss and tinnitus, respectively. Future studies should investigate these genes and if replicated, identify their potential impact on preventive strategies.
顺铂是多种癌症一线化疗的关键组成部分，但会导致周围感觉神经病变、听力损失和耳鸣。我们旨在确定大量接受类似治疗的患者中，与顺铂诱导的神经毒性相关的合并症，而不受颅放疗的混杂影响。
我们利用线性和逻辑回归分析，对 1680 名特征明确的顺铂治疗睾丸癌幸存者进行分析，研究听力损失、耳鸣和周围神经病变与非遗传合并症之间的关系。对每种表型进行全基因组关联研究和基于基因的分析。
听力损失、耳鸣和周围神经病变与年龄和顺铂剂量相关，且相互依存。有这些神经毒性的幸存者经历了更多的高血压和较差的自我报告健康状况。此外，听力损失与临床评估时的 BMI 和非工作相关的噪音暴露（>5 小时/周）呈正相关。耳鸣与吸烟、高胆固醇血症和噪音暴露呈正相关。我们观察到周围神经病变与持续性眩晕、吸烟和过量饮酒之间存在正相关。听力损失和 TXNRD1（在氧化还原调节中起关键作用）在基于基因的分析中与边缘显著（p=4.2×10）。先前发现与听力损失显著相关（n=511）的 WFS1 中的 rs62283056 ，在独立的复制队列中具有边缘显著意义（p=0.06；n=606）。基于基因的分析表明，耳鸣与 WNT8A（编码生殖细胞肿瘤中重要的信号蛋白）之间存在显著关联（p=2.5×10）。
TXNRD1 和 WNT8A 中的遗传变异分别是听力损失和耳鸣的显著风险因素。未来的研究应调查这些基因，如果得到复制，确定它们对预防策略的潜在影响。
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