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JAMA Oncol. 2017 Nov 1;3(11):1558-1562. doi: 10.1001/jamaoncol.2017.0502.

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

Author information

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

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.

PMID:
28448657
PMCID:
PMC5824214
DOI:
10.1001/jamaoncol.2017.0502
[Indexed for MEDLINE]
Free PMC Article

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