title: Genetic variants in TPMT and COMT are associated with hearing loss in children receiving cisplatin chemotherapy.
abstract: Cisplatin is a widely used and effective chemotherapeutic agent, although its use is restricted by the high incidence of irreversible ototoxicity associated with it. In children, cisplatin ototoxicity is a serious and pervasive problem, affecting more than 60% of those receiving cisplatin and compromising language and cognitive development. Candidate gene studies have previously reported associations of cisplatin ototoxicity with genetic variants in the genes encoding glutathione S-transferases and megalin. We report association analyses for 220 drug-metabolism genes in genetic susceptibility to cisplatin-induced hearing loss in children. We genotyped 1,949 SNPs in these candidate genes in an initial cohort of 54 children treated in pediatric oncology units, with replication in a second cohort of 112 children recruited through a national surveillance network for adverse drug reactions in Canada. We identified genetic variants in TPMT (rs12201199, P value = 0.00022, OR = 17.0, 95% CI 2.3-125.9) and COMT (rs9332377, P value = 0.00018, OR = 5.5, 95% CI 1.9-15.9) associated with cisplatin-induced hearing loss in children.
authors.affiliation: Department of Medical Genetics, University of British Columbia, Centre for Molecular Medicine and Therapeutics, Vancouver, British Columbia, Canada.
authors.forename: Colin J D
authors.initials: CJ
authors.lastname: Ross
authors.forename: Hagit
authors.initials: H
authors.lastname: Katzov-Eckert
authors.forename: Marie-Pierre
authors.initials: MP
authors.lastname: Dubé
authors.forename: Beth
authors.initials: B
authors.lastname: Brooks
authors.forename: S Rod
authors.initials: SR
authors.lastname: Rassekh
authors.forename: Amina
authors.initials: A
authors.lastname: Barhdadi
authors.forename: Yassamin
authors.initials: Y
authors.lastname: Feroz-Zada
authors.forename: Henk
authors.initials: H
authors.lastname: Visscher
authors.forename: Andrew M K
authors.initials: AM
authors.lastname: Brown
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Rieder
authors.forename: Paul C
authors.initials: PC
authors.lastname: Rogers
authors.forename: Michael S
authors.initials: MS
authors.lastname: Phillips
authors.forename: Bruce C
authors.initials: BC
authors.lastname: Carleton
authors.forename: Michael R
authors.initials: MR
authors.lastname: Hayden
mesh_terms: D000970:Antineoplastic Agents / Q000009:adverse effects* / Q000627:therapeutic use; D002394:Catechol O-Methyltransferase / Q000235:genetics*; D002648:Child; D002945:Cisplatin / Q000009:adverse effects* / Q000627:therapeutic use; D015331:Cohort Studies; D014644:Genetic Variation; D034381:Hearing Loss / Q000139:chemically induced / Q000235:genetics*; D006801:Humans; D008780:Methyltransferases / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide
chemical_list: D000970:Antineoplastic Agents; D008780:Methyltransferases; D002394:Catechol O-Methyltransferase; C022745:thiopurine methyltransferase; D002945:Cisplatin