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Brief Report
November 2017

Association Between SLC16A5 Genetic Variation and Cisplatin-Induced Ototoxic Effects in Adult Patients With Testicular Cancer

Author Affiliations
  • 1Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver, British Columbia, Canada
  • 2BC Children’s Hospital Research Institute, Vancouver, British Columbia, Canada
  • 3Tom Baker Cancer Centre, Calgary, Alberta, Canada
  • 4Division of Translational Therapeutics, Department of Pediatrics, Faculty of Medicine, University of British Columbia, Vancouver, British Columbia, Canada
  • 5Pharmaceutical Outcomes Programme, BC Children’s Hospital, Vancouver, British Columbia, Canada
  • 6Audiology and Speech Pathology Department, BC Children’s Hospital, Vancouver, British Columbia, Canada
  • 7Department of Medical Genetics, Centre for Molecular Medicine and Therapeutics, Faculty of Medicine, University of British Columbia, Vancouver, British Columbia, Canada
  • 8Medical Oncology and Hematology, Department of Medicine, Princess Margaret Cancer Centre – University Health Network and University of Toronto, Toronto, Ontario, Canada
  • 9BC Cancer Agency and University of British Columbia, Vancouver, British Columbia, Canada
  • 10Princess Margaret Cancer Centre and University of Toronto, Toronto, Ontario, Canada
  • 11University Institute of Clinical Chemistry, Inselspital Bern University Hospital and University of Bern, Bern, Switzerland
  • 12Neuro-Otology Unit, Vancouver General Hospital, Vancouver, British Columbia, Canada
  • 13Department of Medicine, Centre for Heart Lung Innovation, University of British Columbia, Vancouver, British Columbia, Canada
  • 14Translational Laboratory in Genetic Medicine, Agency for Science Technology and Research (A*STAR), Singapore
JAMA Oncol. 2017;3(11):1558-1562. doi:10.1001/jamaoncol.2017.0502
Key Points

Question  Do genetic polymorphisms contribute to the development of cisplatin-induced ototoxic effects?

Findings  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.

Meaning  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.

Abstract

Importance  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.

Objective  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.

Exposures  Cisplatin-based chemotherapy.

Main Outcomes and Measures  Cisplatin-induced ototoxic effects.

Results  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.

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