title: Replication of TPMT and ABCC3 genetic variants highly associated with cisplatin-induced hearing loss in children.
abstract: 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.
authors.affiliation: Department of Medical Genetics, Centre for Molecular Medicine and Therapeutics, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: K
authors.initials: K
authors.lastname: Pussegoda
authors.forename: C J
authors.initials: CJ
authors.lastname: Ross
authors.forename: H
authors.initials: H
authors.lastname: Visscher
authors.forename: M
authors.initials: M
authors.lastname: Yazdanpanah
authors.forename: B
authors.initials: B
authors.lastname: Brooks
authors.forename: S R
authors.initials: SR
authors.lastname: Rassekh
authors.forename: Y F
authors.initials: YF
authors.lastname: Zada
authors.forename: M-P
authors.initials: MP
authors.lastname: Dubé
authors.forename: B C
authors.initials: BC
authors.lastname: Carleton
authors.forename: M R
authors.initials: MR
authors.lastname: Hayden
mesh_terms: D000293:Adolescent; D000367:Age Factors; D000970:Antineoplastic Agents / Q000633:toxicity*; D002394:Catechol O-Methyltransferase / Q000235:genetics; D002648:Child; D002675:Child, Preschool; D002945:Cisplatin / Q000633:toxicity*; D061888:Craniospinal Irradiation; D004305:Dose-Response Relationship, Drug; D005260:Female; D014644:Genetic Variation; D005838:Genotype; D034381:Hearing Loss / Q000139:chemically induced*; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D008780:Methyltransferases / Q000235:genetics*; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000235:genetics*; D012307:Risk Factors; D012680:Sensitivity and Specificity
chemical_list: D000970:Antineoplastic Agents; D002394:Catechol O-Methyltransferase; D002945:Cisplatin; D008780:Methyltransferases; D027425:ATP-Binding Cassette, Sub-Family C Proteins; C114462:multidrug resistance-associated protein 3; C022745:thiopurine methyltransferase