AUTHOR=Hurkmans Evelien G. E. , Klumpers Marije J. , Dello Russo Cinzia , De Witte Ward , Guchelaar Henk-Jan , Gelderblom Hans , Cleton-Jansen Anne-Marie , Vermeulen Sita H. , Kaal Suzanne , van der Graaf Winette T. A. , Flucke Uta , Gidding Corrie E. M. , Schreuder Hendrik W. B. , de Bont Eveline S. J. M. , Caron Huib N. , Gattuso Giovanna , Schiavello Elisabetta , Terenziani Monica , Massimino Maura , McCowage Geoff , Nagabushan Sumanth , Limaye Anuja , Rose Victoria , Catchpoole Daniel , Jorgensen Andrea L. , Barton Christopher , Delaney Lucy , Hawcutt Daniel B. , Pirmohamed Munir , Pizer Barry , Coenen Marieke J. H. , te Loo D. Maroeska W. M. TITLE=Genome-wide analyses of platinum-induced ototoxicity in childhood cancer patients: Results of GO-CAT and United Kingdom MAGIC consortia JOURNAL=Frontiers in Pharmacology VOLUME=13 YEAR=2023 URL=https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2022.980309 DOI=10.3389/fphar.2022.980309 ISSN=1663-9812 ABSTRACT=

Hearing loss (ototoxicity) is a major adverse effect of cisplatin and carboplatin chemotherapy. The aim of this study is to identify novel genetic variants that play a role in platinum-induced ototoxicity. Therefore, a genome-wide association study was performed in the Genetics of Childhood Cancer Treatment (GO-CAT) cohort (n = 261) and the United Kingdom Molecular Genetics of Adverse Drug Reactions in Children Study (United Kingdom MAGIC) cohort (n = 248). Results of both cohorts were combined in a meta-analysis. In primary analysis, patients with SIOP Boston Ototoxicity Scale grade ≥1 were considered cases, and patients with grade 0 were controls. Variants with a p-value <10−5 were replicated in previously published data by the PanCareLIFE cohort (n = 390). No genome-wide significant associations were found, but variants in TSPAN5, RBBP4P5, AC010090.1 and RNU6-38P were suggestively associated with platinum-induced ototoxicity. The lowest p-value was found for rs7671702 in TSPAN5 (odds ratio 2.0 (95% confidence interval 1.5–2.7), p-value 5.0 × 10−7). None of the associations were significant in the replication cohort, although the effect directions were consistent among all cohorts. Validation and functional understanding of these genetic variants could lead to more insights in the development of platinum-induced ototoxicity.