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Personalized Medicine and Imaging

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

Britt I. Drögemöller, Beth Brooks, Carol Critchley, José G. Monzon, Galen E.B. Wright, Geoffrey Liu, Daniel J. Renouf, Christian K. Kollmannsberger, Philippe L. Bedard, Michael R. Hayden, Karen A. Gelmon, Bruce C. Carleton and Colin J.D. Ross
Britt I. Drögemöller
Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver, British Columbia, Canada.BC Children's Hospital Research Institute, Vancouver, British Columbia, Canada.
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Beth Brooks
Audiology and Speech Pathology Department, BC Children's Hospital, Vancouver, British Columbia, Canada.
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Carol Critchley
Neuro-Otology Unit, Vancouver General Hospital, Vancouver, British Columbia, Canada.
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José G. Monzon
Tom Baker Cancer Centre, Calgary, AB, Canada.
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Galen E.B. Wright
BC Children's Hospital Research Institute, Vancouver, British Columbia, Canada.Department of Medical Genetics, Centre for Molecular Medicine and Therapeutics, Faculty of Medicine, University of British Columbia, Vancouver, British Columbia, Canada.
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Geoffrey Liu
Medical Oncology and Hematology, Department of Medicine, Princess Margaret Cancer Centre–University Health Network and University of Toronto, Toronto, Ontario, Canada.
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Daniel J. Renouf
BC Cancer Agency and University of British Columbia, Vancouver, British Columbia, Canada.
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Christian K. Kollmannsberger
BC Cancer Agency and University of British Columbia, Vancouver, British Columbia, Canada.
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Philippe L. Bedard
Princess Margaret Cancer Centre and University of Toronto, Toronto, Ontario, Canada.
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Michael R. Hayden
BC Children's Hospital Research Institute, Vancouver, British Columbia, Canada.Department of Medical Genetics, Centre for Molecular Medicine and Therapeutics, Faculty of Medicine, University of British Columbia, Vancouver, British Columbia, Canada.
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Karen A. Gelmon
BC Cancer Agency and University of British Columbia, Vancouver, British Columbia, Canada.
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Bruce C. Carleton
Division of Translational Therapeutics, Department of Pediatrics, Faculty of Medicine, University of British Columbia, Vancouver, British Columbia, Canada.Pharmaceutical Outcomes Programme, BC Children's Hospital, Vancouver, BC, Canada.
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Colin J.D. Ross
Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver, British Columbia, Canada.BC Children's Hospital Research Institute, Vancouver, British Columbia, Canada.
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  • For correspondence: colin.ross@ubc.ca
DOI: 10.1158/1078-0432.CCR-17-2810 Published April 2018
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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.

Footnotes

  • Note: Supplementary data for this article are available at Clinical Cancer Research Online (http://clincancerres.aacrjournals.org/).

  • K.A. Gelmon, B.C. Carleton, and C.J.D. Ross jointly supervised this work.

  • ↵†Deceased.

  • Received September 26, 2017.
  • Revision received December 1, 2017.
  • Accepted January 16, 2018.
  • Published first January 22, 2018.
  • ©2018 American Association for Cancer Research.
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Clinical Cancer Research: 24 (8)
April 2018
Volume 24, Issue 8
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Further Investigation of the Role of ACYP2 and WFS1 Pharmacogenomic Variants in the Development of Cisplatin-Induced Ototoxicity in Testicular Cancer Patients
Britt I. Drögemöller, Beth Brooks, Carol Critchley, José G. Monzon, Galen E.B. Wright, Geoffrey Liu, Daniel J. Renouf, Christian K. Kollmannsberger, Philippe L. Bedard, Michael R. Hayden, Karen A. Gelmon, Bruce C. Carleton and Colin J.D. Ross
Clin Cancer Res April 15 2018 (24) (8) 1866-1871; DOI: 10.1158/1078-0432.CCR-17-2810

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Further Investigation of the Role of ACYP2 and WFS1 Pharmacogenomic Variants in the Development of Cisplatin-Induced Ototoxicity in Testicular Cancer Patients
Britt I. Drögemöller, Beth Brooks, Carol Critchley, José G. Monzon, Galen E.B. Wright, Geoffrey Liu, Daniel J. Renouf, Christian K. Kollmannsberger, Philippe L. Bedard, Michael R. Hayden, Karen A. Gelmon, Bruce C. Carleton and Colin J.D. Ross
Clin Cancer Res April 15 2018 (24) (8) 1866-1871; DOI: 10.1158/1078-0432.CCR-17-2810
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Clinical Cancer Research
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