TY - JOUR
T1 - Genome-wide analyses of platinum-induced ototoxicity in childhood cancer patients
T2 - Results of GO-CAT and United Kingdom MAGIC consortia
AU - Hurkmans, Evelien G.E.
AU - Klumpers, Marije J.
AU - Dello Russo, Cinzia
AU - De Witte, Ward
AU - Guchelaar, Henk Jan
AU - Gelderblom, Hans
AU - Cleton-Jansen, Anne Marie
AU - Vermeulen, Sita H.
AU - Kaal, Suzanne
AU - van der Graaf, Winette T.A.
AU - Flucke, Uta
AU - Gidding, Corrie E.M.
AU - Schreuder, Hendrik W.B.
AU - de Bont, Eveline S.J.M.
AU - Caron, Huib N.
AU - Gattuso, Giovanna
AU - Schiavello, Elisabetta
AU - Terenziani, Monica
AU - Massimino, Maura
AU - McCowage, Geoff
AU - Nagabushan, Sumanth
AU - Limaye, Anuja
AU - Rose, Victoria
AU - Catchpoole, Daniel
AU - Jorgensen, Andrea L.
AU - Barton, Christopher
AU - Delaney, Lucy
AU - Hawcutt, Daniel B.
AU - Pirmohamed, Munir
AU - Pizer, Barry
AU - Coenen, Marieke J.H.
AU - te Loo, D. Maroeska W.M.
N1 - Publisher Copyright:
Copyright © 2023 Hurkmans, Klumpers, Dello Russo, De Witte, Guchelaar, Gelderblom, Cleton-Jansen, Vermeulen, Kaal, van der Graaf, Flucke, Gidding, Schreuder, de Bont, Caron, Gattuso, Schiavello, Terenziani, Massimino, McCowage, Nagabushan, Limaye, Rose, Catchpoole, Jorgensen, Barton, Delaney, Hawcutt, Pirmohamed, Pizer, Coenen and te Loo.
PY - 2023/1/9
Y1 - 2023/1/9
N2 - 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.
AB - 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.
KW - carboplatin
KW - childhood cancer
KW - cisplatin
KW - GWAS
KW - ototoxicity
KW - TSPAN5
UR - http://www.scopus.com/inward/record.url?scp=85146916438&partnerID=8YFLogxK
U2 - 10.3389/fphar.2022.980309
DO - 10.3389/fphar.2022.980309
M3 - Article
AN - SCOPUS:85146916438
SN - 1663-9812
VL - 13
JO - Frontiers in Pharmacology
JF - Frontiers in Pharmacology
M1 - 980309
ER -
