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Clin Cancer Res. 2018 Apr 15;24(8):1866-1871. doi: 10.1158/1078-0432.CCR-17-2810. Epub 2018 Jan 22.

Further Investigation of the Role of ACYP2 and WFS1 Pharmacogenomic Variants in the Development of Cisplatin-Induced Ototoxicity in Testicular Cancer Patients.

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
Audiology and Speech Pathology Department, BC Children's Hospital, Vancouver, British Columbia, Canada.
4
Neuro-Otology Unit, Vancouver General Hospital, Vancouver, British Columbia, Canada.
5
Tom Baker Cancer Centre, Calgary, AB, Canada.
6
Department of Medical Genetics, Centre for Molecular Medicine and Therapeutics, Faculty of Medicine, University of British Columbia, Vancouver, British Columbia, Canada.
7
Medical Oncology and Hematology, Department of Medicine, Princess Margaret Cancer Centre-University Health Network and University of Toronto, Toronto, Ontario, Canada.
8
BC Cancer Agency and University of British Columbia, Vancouver, British Columbia, Canada.
9
Princess Margaret Cancer Centre and University of Toronto, Toronto, Ontario, Canada.
10
Division of Translational Therapeutics, Department of Pediatrics, Faculty of Medicine, University of British Columbia, Vancouver, British Columbia, Canada.
11
Pharmaceutical Outcomes Programme, BC Children's Hospital, Vancouver, BC, Canada.
12
Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver, British Columbia, Canada. colin.ross@ubc.ca.

Abstract

Purpose: Adverse drug reactions such as ototoxicity, which occurs in approximately one-fifth of adult patients who receive cisplatin treatment, can incur large socioeconomic burdens on patients with testicular cancer who develop this cancer during early adulthood. Recent genome-wide association studies have identified genetic variants in ACYP2 and WFS1 that are associated with cisplatin-induced ototoxicity. We sought to explore the role of these genetic susceptibility factors to cisplatin-induced ototoxicity in patients with testicular cancer.Experimental Design: Extensive clinical and demographic data were collected for 229 patients with testicular cancer treated with cisplatin. Patients were genotyped for two variants, ACYP2 rs1872328 and WFS1 rs62283056, that have previously been associated with hearing loss in cisplatin-treated patients. Analyses were performed to investigate the association of these variants with ototoxicity in this cohort of adult patients with testicular cancer.Results: Pharmacogenomic analyses revealed that ACYP2 rs1872328 was significantly associated with cisplatin-induced ototoxicity [P = 2.83 × 10-3, OR (95% CI):14.7 (2.6-84.2)]. WFS1 rs62283056 was not significantly associated with ototoxicity caused by cisplatin (P = 0.39); however, this variant was associated with hearing loss attributable to any cause [P = 5.67 × 10-3, OR (95% CI): 3.2 (1.4-7.7)].Conclusions: This study has provided the first evidence for the role of ACYP2 rs1872328 in cisplatin-induced ototoxicity in patients with testicular cancer. These results support the use of this information to guide the development of strategies to prevent cisplatin-induced ototoxicity across cancers. Further, this study has highlighted the importance of phenotypic differences in replication studies and has provided further evidence for the role of WFS1 rs62283056 in susceptibility to hearing loss, which may be worsened by cisplatin treatment. Clin Cancer Res; 24(8); 1866-71. ©2018 AACR.

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