Journal
CLINICAL PHARMACOLOGY & THERAPEUTICS
Volume 94, Issue 2, Pages 243-251Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/clpt.2013.80
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Funding
- CPNDS adverse drug reaction surveillance network
- peer-reviewed Genome Canada Applied Health Research Program
- Canada Foundation for Innovation
- Canadian Institutes of Health Research
- Regional/National Clinical Research Initiatives
- Genome British Columbia Translational Program for Applied Health
- Child & Family Research Institute
- Faculties of Pharmaceutical Sciences and Medicine, University of British Columbia
- University of Western Ontario
- Canada Gene Cure Foundation
- Canadian Society of Clinical Pharmacology
- C17 Research Network
- Childhood Cancer Foundation-Candlelighters Canada
- Canadian Paediatric Society, Merck Frosst
- Eli Lilly
- Pfizer
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Cisplatin is a widely used chemotherapeutic agent for the treatment of solid tumors. A serious complication of cisplatin treatment is permanent hearing loss. The aim of this study was to replicate previous genetic findings in an independent cohort of 155 pediatric patients. Associations were replicated for genetic variants in TPMT (rs12201199, P = 0.0013, odds ratio (OR) 6.1) and ABCC3 (rs1051640, P = 0.036, OR 1.8). A predictive model combining variants in TPMT, ABCC3, and COMT with clinical variables (patient age, vincristine treatment, germ-cell tumor, and cranial irradiation) significantly improved the prediction of hearing-loss development as compared with using clinical risk factors alone (area under the curve (AUC) 0.786 vs. 0.708, P = 0.00048). The novel combination of genetic and clinical factors predicted the risk of hearing loss with a sensitivity of 50.3% and a specificity of 92.7%. These findings provide evidence to support the importance of TPMT, COMT, and ABCC3 in the prediction of cisplatin-induced hearing loss in children.
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