Genome-wide analyses of platinum-induced ototoxicity in childhood cancer patients: Results of GO-CAT and United Kingdom MAGIC consortia
| Autor: | Hurkmans, E.G.E., Klumpers, M.J., Dello Russo, C., Witte, W. de, Guchelaar, H.J., Gelderblom, H., Cleton-Jansen, A.M., Vermeulen, S.H., Kaal, S., Graaf, W.T.A. van der, Flucke, U., Gidding, C.E.M., Schreuder, H.W.B., Bont, E.S.J.M. de, Caron, H.N., Gattuso, G., Schiavello, E., Terenziani, M., Massimino, M., McCowage, G., Nagabushan, S., Limaye, A., Rose, V., Catchpoole, D., Jorgensen, A.L., Barton, C., Delaney, L., Hawcutt, D.B., Pirmohamed, M., Pizer, B., Coenen, M.J.H., Loo, D.M.W.M. te |
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| Rok vydání: | 2023 |
| Předmět: |
Pharmacology
Settore BIO/14 - FARMACOLOGIA TSPAN5 Vascular damage Radboud Institute for Health Sciences [Radboudumc 16] cisplatin Rare cancers Radboud Institute for Molecular Life Sciences [Radboudumc 9] Reconstructive and regenerative medicine Radboud Institute for Health Sciences [Radboudumc 10] ototoxicity All institutes and research themes of the Radboud University Medical Center Urological cancers Radboud Institute for Health Sciences [Radboudumc 15] carboplatin Inflammatory diseases Radboud Institute for Health Sciences [Radboudumc 5] childhood cancer GWAS Pharmacology (medical) Rare cancers Radboud Institute for Health Sciences [Radboudumc 9] |
| Zdroj: | Frontiers in Pharmacology, 13 Frontiers in Pharmacology, 13. FRONTIERS MEDIA SA |
| Popis: | 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 −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. |
| Databáze: | OpenAIRE |
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