Frontiers in Pharmacology (Jan 2023)
Genome-wide analyses of platinum-induced ototoxicity in childhood cancer patients: Results of GO-CAT and United Kingdom MAGIC consortia
- Evelien G. E. Hurkmans,
- Marije J. Klumpers,
- Cinzia Dello Russo,
- Cinzia Dello Russo,
- Ward De Witte,
- Henk-Jan Guchelaar,
- Hans Gelderblom,
- Anne-Marie Cleton-Jansen,
- Sita H. Vermeulen,
- Suzanne Kaal,
- Winette T. A. van der Graaf,
- Winette T. A. van der Graaf,
- Uta Flucke,
- Corrie E. M. Gidding,
- Hendrik W. B. Schreuder,
- Eveline S. J. M. de Bont,
- Huib N. Caron,
- Giovanna Gattuso,
- Elisabetta Schiavello,
- Monica Terenziani,
- Maura Massimino,
- Geoff McCowage,
- Sumanth Nagabushan,
- Sumanth Nagabushan,
- Anuja Limaye,
- Victoria Rose,
- Daniel Catchpoole,
- Andrea L. Jorgensen,
- Christopher Barton,
- Lucy Delaney,
- Daniel B. Hawcutt,
- Daniel B. Hawcutt,
- Munir Pirmohamed,
- Barry Pizer,
- Marieke J. H. Coenen,
- D. Maroeska W. M. te Loo
Affiliations
- Evelien G. E. Hurkmans
- Department of Human Genetics, Radboud University Medical Center, Nijmegen, Netherlands
- Marije J. Klumpers
- Department of Pediatrics, Radboud University Medical Center, Nijmegen, Netherlands
- Cinzia Dello Russo
- Department of Pharmacology and Therapeutics, Institute of Systems, Molecular and Integrative Biology (ISMIB), University of Liverpool, Liverpool, United Kingdom
- Cinzia Dello Russo
- Department of Healthcare Surveillance and Bioethics, Section of Pharmacology, Università Cattolica del Sacro Cuore-Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy
- Ward De Witte
- Department of Human Genetics, Radboud University Medical Center, Nijmegen, Netherlands
- Henk-Jan Guchelaar
- Department of Clinical Pharmacy & Toxicology, Leiden University Medical Center, Leiden, Netherlands
- Hans Gelderblom
- Department of Medical Oncology, Leiden University Medical Center, Leiden, Netherlands
- Anne-Marie Cleton-Jansen
- Department of Pathology, Leiden University Medical Center, Leiden, Netherlands
- Sita H. Vermeulen
- Department for Health Evidence, Radboud University Medical Center, Nijmegen, Netherlands
- Suzanne Kaal
- Department of Medical Oncology, Radboud University Medical Center, Nijmegen, Netherlands
- Winette T. A. van der Graaf
- Department of Medical Oncology, Radboud University Medical Center, Nijmegen, Netherlands
- Winette T. A. van der Graaf
- 0Department of Medical Oncology, Netherlands Cancer Institute, Amsterdam, Netherlands
- Uta Flucke
- 1Department of Pathology, Radboud University Medical Center, Nijmegen, Netherlands
- Corrie E. M. Gidding
- 2Princess Maxima Center for Pediatric Oncology, Utrecht, Netherlands
- Hendrik W. B. Schreuder
- 3Department of Orthopedics, Radboud University Medical Center, Nijmegen, Netherlands
- Eveline S. J. M. de Bont
- 4Department of Pediatrics, Beatrix Children’s Hospital, University Medical Center Groningen, Groningen, Netherlands
- Huib N. Caron
- 5Department of Pediatrics, Amsterdam University Medical Centers, Emma Children’s Hospital, Amsterdam, Netherlands
- Giovanna Gattuso
- 6Pediatric Oncology Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
- Elisabetta Schiavello
- 6Pediatric Oncology Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
- Monica Terenziani
- 6Pediatric Oncology Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
- Maura Massimino
- 6Pediatric Oncology Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
- Geoff McCowage
- 7Cancer Centre for Children, The Children’s Hospital at Westmead, Sydney, NSW, Australia
- Sumanth Nagabushan
- 7Cancer Centre for Children, The Children’s Hospital at Westmead, Sydney, NSW, Australia
- Sumanth Nagabushan
- 8Discipline of Child and Adolescent Health, University of Sydney, Sydney, NSW, Australia
- Anuja Limaye
- 9Department of Audiology, The Children’s Hospital at Westmead, Sydney, NSW, Australia
- Victoria Rose
- 0Department of Neuro-Otology, Royal Prince Alfred Hospital, University of Sydney, Sydney, NSW, Australia
- Daniel Catchpoole
- 1Children’s Cancer Research Unit, The Children’s Hospital at Westmead, Sydney, NSW, Australia
- Andrea L. Jorgensen
- 2Department of Health Data Science, University of Liverpool, Liverpool, United Kingdom
- Christopher Barton
- 3Department of Women’s and Children’s Health, University of Liverpool, Liverpool, United Kingdom
- Lucy Delaney
- 3Department of Women’s and Children’s Health, University of Liverpool, Liverpool, United Kingdom
- Daniel B. Hawcutt
- 3Department of Women’s and Children’s Health, University of Liverpool, Liverpool, United Kingdom
- Daniel B. Hawcutt
- 4NIHR Alder Hey Clinical Research Facility, Alder Hey Children’s Hospital, Liverpool, United Kingdom
- Munir Pirmohamed
- 5Department of Pharmacology and Therapeutics, University of Liverpool, Liverpool, United Kingdom
- Barry Pizer
- 6Department of Pediatric Oncology, Alder Hey Children’s Hospital, Liverpool, United Kingdom
- Marieke J. H. Coenen
- Department of Human Genetics, Radboud University Medical Center, Nijmegen, Netherlands
- D. Maroeska W. M. te Loo
- Department of Pediatrics, Radboud University Medical Center, Nijmegen, Netherlands
- DOI
- https://doi.org/10.3389/fphar.2022.980309
- Journal volume & issue
-
Vol. 13
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.
Keywords
