Do genetic polymorphisms contribute to the development of cisplatin-induced ototoxic effects?
In this pharmacogenomic case-control association study of adult patients with testicular cancer treated with cisplatin, patients carrying a genetic variant in SLC16A5 were significantly less likely to experience ototoxic effects. These findings were validated through independent replication, 2 functional assays, and literature reporting that cimetidine, an SLC16A5-inhibitor, prevents cisplatin-induced ototoxic effects in mice.
To our knowledge, this is the first report of an association between a genetic variant in SLC16A5 and cisplatin-induced ototoxic effects; this variant can be used to aid in predicting risk of ototoxic effects.
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.
Main Outcomes and Measures
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.
Conclusions and Relevance
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.
Drögemöller BI, Monzon JG, Bhavsar AP, Borrie AE, Brooks B, Wright GEB, Liu G, Renouf DJ, Kollmannsberger CK, Bedard PL, Aminkeng F, Amstutz U, Hildebrand CA, Gunaretnam EP, Critchley C, Chen Z, Brunham LR, Hayden MR, Ross CJD, Gelmon KA, Carleton BC. Association Between SLC16A5 Genetic Variation and Cisplatin-Induced Ototoxic Effects in Adult Patients With Testicular Cancer. JAMA Oncol. 2017;3(11):1558–1562. doi:10.1001/jamaoncol.2017.0502
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