Letter abstract


Nature Genetics 41, 1345 - 1349 (2009)
Published online: 8 November 2009 | Corrected online: 21 March 2013 | doi:10.1038/ng.478

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

Colin J D Ross1,2,11, Hagit Katzov-Eckert1,2,11, Marie-Pierre Dubé3, Beth Brooks4, S Rod Rassekh5, Amina Barhdadi3, Yassamin Feroz-Zada3, Henk Visscher1,2, Andrew M K Brown3,6, Michael J Rieder7, Paul C Rogers5, Michael S Phillips3,6, Bruce C Carleton2,8,9, Michael R Hayden1,2 & the CPNDS Consortium10

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Cisplatin is a widely used and effective chemotherapeutic agent, although its use is restricted by the high incidence of irreversible ototoxicity associated with it1. In children, cisplatin ototoxicity is a serious and pervasive problem, affecting more than 60% of those receiving cisplatin2, 3, 4, 5 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 megalin6, 7, 8. 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.

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  1. Department of Medical Genetics, University of British Columbia, Centre for Molecular Medicine and Therapeutics, Vancouver, British Columbia, Canada.
  2. Child and Family Research Institute, Children's and Women's Health Research Centre of British Columbia, Vancouver, British Columbia, Canada.
  3. Montreal Heart Institute and Université de Montreal, Montreal, Quebec, Canada.
  4. Audiology and Speech Pathology Department British Columbia Children's Hospital, Vancouver, British Columbia, Canada.
  5. Department of Pediatrics, Division of Pediatric Hematology/Oncology/Bone and Marrow Transplant, British Columbia Children's Hospital, Vancouver, British Columbia, Canada.
  6. Montreal Heart Institute and Genome Québec Pharmacogenomics Centre, Montreal, Quebec, Canada.
  7. Department of Paediatrics, Children's Hospital at the London Health Sciences Centre, London, UK.
  8. Faculty of Pharmaceutical Sciences University of British Columbia, Vancouver, British Columbia, Canada.
  9. Department of Paediatrics, Pharmaceutical Outcomes Programme, University of British Columbia, Vancouver, British Columbia, Canada.
  10. A full list of members is provided in the Supplementary Note.
  11. These authors contributed equally to this work.

Correspondence to: Michael R Hayden1,2 e-mail: mrh@cmmt.ubc.ca

* In the version of this article initially published, the units for treatment duration in Table 1 were incorrectly given as weeks rather than months. This error has been corrected in the HTML and PDF versions of the article.

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