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PMID: 19898482 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

Genetic variants in TPMT and COMT are associated with hearing loss in children receiving cisplatin chemotherapy.

Nature genetics ·Vol. 41 ·No. 12 ·2009-12-00 ·Pages 1345-9

Ross CJ, Katzov-Eckert H, Dubé MP, Brooks B, Rassekh SR, Barhdadi A, Feroz-Zada Y, Visscher H, Brown AM, Rieder MJ, Rogers PC, Phillips MS, Carleton BC, Hayden MR, CPNDS Consortium

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.

MeSH Terms
Antineoplastic Agents/adverse effects,therapeutic use Catechol O-Methyltransferase/genetics Child Cisplatin/adverse effects,therapeutic use Cohort Studies Genetic Variation Hearing Loss/chemically induced,genetics Humans Methyltransferases/genetics Polymorphism, Single Nucleotide
Chemicals
Antineoplastic Agents Methyltransferases Catechol O-Methyltransferase thiopurine methyltransferase Cisplatin
Authors & Affiliations
15 authors, click to expand affiliations / ORCID
Ross Colin J D
Department of Medical Genetics, University of British Columbia, Centre for Molecular Medicine and Therapeutics, Vancouver, British Columbia, Canada.
Katzov-Eckert Hagit
Dubé Marie-Pierre
Brooks Beth
Rassekh S Rod
Barhdadi Amina
Feroz-Zada Yassamin
Visscher Henk
Brown Andrew M K
Rieder Michael J
Rogers Paul C
Phillips Michael S
Carleton Bruce C
Hayden Michael R
CPNDS Consortium
Investigators
61 investigators, click to expand
Hayden Michael
Carleton Bruce
Ross Colin
Smith Anne
MacLeod Stuart
Wasserman Wyeth
Hildebrand Claudette
Castro Lucila
Ghannadan Reza
Carter Catherine
Honeyman Graeme
Katzov Hagit
Rassekh Rod
Lau Lily
Lim Jonathan
Miao Fudan
Mitton Craig
Ng Dawn
Pape Terry
Stannard Peter
Visscher Henk
Zhang Lin Hwa
Nijssen-Jordan Cheri
Johnson David
Verbeek Linda
Kaczowka Rick
Churcher Linda
Grundy Paul
Stobart Kent
Wilson Bev
Desai Sunil
Hall Kevin
Chan Shanna
Grarnham Byron
Staub Michelle
Rieder Michael
Malkin Becky
Madadi Parvaz
Cranston Amy
Portwine Carol
Koren Gideon
Ito Shinya
Garcia Facundo
Inoue Miho
Sakaguchi Sachi
Tanaka Toshihiro
Vaillancourt Regis
Elliott-Miller Pat
Mankoo Herpreet
Wong Elaine
Wilson Brenda
Maher Maurica
Bussières Jean-Francois
Lebel Denis
Barret Pierre
Dubé Marie-Pierre
Phillips Michael
Avard Denise
Murray Margaret
Boliver Darlene
Osborne Carol-anne
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Article Info
Journal
Nature genetics
Abbr.
Nat Genet
ISSN
1546-1718
DOI
10.1038/ng.478
Published
2009-12-00
Epub
2009-00-08
Pages
1345-9
Language
English
Region
United States
NLM ID
9216904
Subset
IM
Grants
Canadian Institutes of Health Research · Canada
Corrections
ErratumIn
-
CommentIn
PMID: 20597921
CommentIn
PMID: 24241639
External Links
PubMed source DOI: 10.1038/ng.478 View journal details
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