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

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  • A Corrigendum to this article was published on 26 April 2013

Abstract

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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Figure 1: Cisplatin ototoxity and number of risk alleles.

Change history

  • 21 March 2013

    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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Acknowledgements

We especially want to acknowledge the study participants and their families for their participation in the Canadian Pharmacogenomics Network for Drug Safety (CPNDS) network; this work could not have been done without your help and support. We also want to acknowledge the support of the CPNDS active ADR surveillance consortium, as well as S. Langlois and B. Casey (Supplementary Note). The study was funded by Genome Canada, and additional funding was also provided by Genome British Columbia, Child and Family Research Institute, University of British Columbia Faculty of Pharmaceutical Sciences, Canadian Institutes of Health Research, Canada Foundation for Innovation, Canada Gene Cure Foundation, Canadian Society of Clinical Pharmacology, BC Clinical Genomics Network, C17 Research Network and Childhood Cancer Foundation–Candlelighters Canada, Michael Smith Foundation for Health Research, Health Canada, Pfizer, Eli Lilly, Merck Frosst and Janssen-Ortho. This work was funded as part of the peer-reviewed Genome Canada Applied Health Research Program; the pharmaceutical industry partners had no formal or informal role in this program of research.

Author information

B.C.C., S.R.R., M.J.R., P.C.R. and members of the CPNDS consortium recruited subject cohorts. B.B., B.C.C. and S.R.R. phenotyped subject cohorts. C.J.D.R., H.K.-E., H.V., A.M.K.B. and M.S.P. designed and performed genotyping studies. C.J.D.R., H.K.-E., H.V., A.B., Y.F.-Z. and M.-P.D. analyzed genotyping data. B.C.C. and M.R.H. planned and coordinated the study. All authors contributed to the final version of the manuscript.

Correspondence to Michael R Hayden.

Additional information

A full list of members is provided in the Supplementary Note.

Supplementary information

Supplementary Text and Figures

Supplementary Note, Supplementary Figures 1 and 2 and Supplementary Tables 2–5. (PDF 782 kb)

Supplementary Table 1

Allele frequencies and results of the case-control tests of association (XLS 803 kb)

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Ross, C., Katzov-Eckert, H., Dubé, M. et al. Genetic variants in TPMT and COMT are associated with hearing loss in children receiving cisplatin chemotherapy. Nat Genet 41, 1345–1349 (2009) doi:10.1038/ng.478

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