Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver, British Columbia, Canada.
BC Children's Hospital Research Institute, Vancouver, British Columbia, Canada.
JAMA Oncol. 2017 Nov 1;3(11):1558-1562. doi: 10.1001/jamaoncol.2017.0502.
Cisplatin-induced ototoxic effects are an important complication that affects testicular cancer survivors as a consequence of treatment. The identification of genetic variants associated with this adverse drug reaction will further our mechanistic understanding of its development and potentially lead to strategies to prevent ototoxic effects.
To identify the genetic variants associated with cisplatin-induced ototoxic effects in adult testicular cancer patients.
DESIGN, SETTING, AND PARTICIPANTS: This retrospective study was performed by the Canadian Pharmacogenomics Network for Drug Safety using patients recruited from 5 adult oncology treatment centers across Canada. Male patients who were 17 years or older, diagnosed with germ cell testicular cancer, and previously treated with cisplatin-based chemotherapy were recruited from July 2009 to April 2013 using active surveillance methodology. Cisplatin-induced ototoxic effects were independently diagnosed by 2 audiologists. Patients were genotyped for 7907 variants using a custom pharmacogenomic array. Logistic regression was used to identify genetic variants that were significantly associated with ototoxic effects. The validity of these findings was confirmed through independent replication and cell-based functional assays.
Cisplatin-based chemotherapy.
Cisplatin-induced ototoxic effects.
After exclusions, 188 patients (median [interquartile range] age, 31 [24-39] years) were enrolled in this study to form the discovery and replication cohorts. Association and fine-mapping analyses identified a protein-coding variant, rs4788863 in SLC16A5, that was associated with protection against cisplatin-induced ototoxic effects in 2 independent cohorts (combined cohort: odds ratio, 0.06; 95% CI, 0.02-0.22; P = 2.17 × 10-7). Functional validation of this transporter gene revealed that in vitro SLC16A5-silencing altered cellular responses to cisplatin treatment, supporting a role for SLC16A5 in the development of cisplatin-induced ototoxic effects. These results were further supported by the literature, which provided confirmatory evidence for the role that SLC16A5 plays in hearing.
This study has identified a novel association between protein-coding variation in SLC16A5 and cisplatin-induced ototoxic effects. These findings have provided insight into the molecular mechanisms of this adverse drug reaction in adult patients with germ cell testicular cancer. Given that previous studies have shown that cimetidine, an SLC16A5-inhibitor, prevents murine cisplatin-induced ototoxic effects, the findings from this study have important implications for otoprotectant strategies in humans.
顺铂引起的耳毒性是一种重要的并发症，会影响睾丸癌幸存者，这是治疗的结果。鉴定与这种药物不良反应相关的遗传变异将进一步加深我们对其发展机制的理解，并可能导致预防耳毒性的策略。
鉴定与成年睾丸癌患者顺铂诱导的耳毒性相关的遗传变异。
设计、地点和参与者：这项回顾性研究由加拿大药物基因组学网络药物安全中心进行，研究对象来自加拿大 5 个成人肿瘤治疗中心。招募了年龄在 17 岁或以上、被诊断为生殖细胞睾丸癌并接受过基于顺铂的化疗的男性患者。使用主动监测方法，从 2009 年 7 月至 2013 年 4 月招募患者。由 2 位听力学家独立诊断顺铂诱导的耳毒性。使用定制的药物基因组学芯片对 7907 个变体进行基因分型。使用逻辑回归鉴定与耳毒性显著相关的遗传变异。通过独立的复制和基于细胞的功能测定验证了这些发现的有效性。
基于顺铂的化疗。
顺铂诱导的耳毒性。
排除后，188 名患者（中位[四分位间距]年龄，31 [24-39] 岁）被纳入本研究，形成发现和复制队列。关联和精细映射分析鉴定出 SLC16A5 中的一个编码蛋白变异 rs4788863，该变异与 2 个独立队列中的顺铂诱导的耳毒性保护相关（合并队列：比值比，0.06；95%CI，0.02-0.22；P=2.17×10-7）。对该转运体基因的功能验证表明，体外 SLC16A5 沉默改变了细胞对顺铂治疗的反应，支持 SLC16A5 在顺铂诱导的耳毒性发展中的作用。文献进一步支持了这一结果，为 SLC16A5 在听力中的作用提供了确证证据。
本研究鉴定了 SLC16A5 编码蛋白变异与顺铂诱导的耳毒性之间的新关联。这些发现为成年生殖细胞睾丸癌患者这种药物不良反应的分子机制提供了深入了解。鉴于先前的研究表明，SLC16A5 抑制剂西咪替丁可预防小鼠顺铂诱导的耳毒性，本研究的发现对人类的耳保护策略具有重要意义。
