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; Ward De Witte; Henk Jan Guchelaar; Hans Gelderblom; Anne Marie Cleton-Jansen; Sita H. Vermeulen; Suzanne Kaal; 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; Anuja Limaye; Victoria Rose; Daniel Catchpoole; Andrea L. Jorgensen; Christopher Barton; Lucy Delaney; Daniel B. Hawcutt; Munir Pirmohamed; Barry Pizer; Marieke J.H. Coenen; D. Maroeska W.M. te Loo

doi:10.3389/fphar.2022.980309

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
, Ward De Witte
, Henk Jan Guchelaar
, Hans Gelderblom
, Anne Marie Cleton-Jansen
, Sita H. Vermeulen
, Suzanne Kaal
, 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, Anuja Limaye, Victoria Rose, Daniel Catchpoole, Andrea L. Jorgensen, Christopher Barton, Lucy Delaney, Daniel B. Hawcutt, Munir Pirmohamed, Barry Pizer, Marieke J.H. Coenen, D. Maroeska W.M. te Loo

Radboud University Nijmegen
University of Liverpool
Catholic University of the Sacred Heart
Leiden University
Netherlands Cancer Institute
Princess Máxima Center for Pediatric Oncology
University of Groningen
University of Amsterdam
IRCCS Fondazione Istituto Nazionale per lo studio e la cura dei tumori - Milano
The Children's Hospital at Westmead
University of Sydney
Royal Prince Alfred Hospital
Alder Hey Children's NHS Foundation Trust

Research output: Contribution to journal › Article › peer-review

6 Citations (Scopus)

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.

Original language	English
Article number	980309
Journal	Frontiers in Pharmacology
Volume	13
DOIs	https://doi.org/10.3389/fphar.2022.980309
Publication status	Published - 9 Jan 2023
Externally published	Yes

Bibliographical note

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.

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

Keywords

carboplatin
childhood cancer
cisplatin
GWAS
ototoxicity
TSPAN5

Access to Document

10.3389/fphar.2022.980309

Cite this

Hurkmans, E. G. E., Klumpers, M. J., Dello Russo, C., De Witte, W., Guchelaar, H. J., Gelderblom, H., Cleton-Jansen, A. M., Vermeulen, S. H., Kaal, S., van der Graaf, W. T. A., Flucke, U., Gidding, C. E. M., Schreuder, H. W. B., de Bont, E. S. J. M., Caron, H. N., Gattuso, G., Schiavello, E., Terenziani, M., Massimino, M., ... te Loo, D. M. W. M. (2023). Genome-wide analyses of platinum-induced ototoxicity in childhood cancer patients: Results of GO-CAT and United Kingdom MAGIC consortia. Frontiers in Pharmacology, 13, Article 980309. https://doi.org/10.3389/fphar.2022.980309

@article{d0b359460a40422b865ed45e76279bae,

title = "Genome-wide analyses of platinum-induced ototoxicity in childhood cancer patients: Results of GO-CAT and United Kingdom MAGIC consortia",

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 = "carboplatin, childhood cancer, cisplatin, GWAS, ototoxicity, TSPAN5",

author = "Hurkmans, \{Evelien G.E.\} and Klumpers, \{Marije J.\} and \{Dello Russo\}, Cinzia and \{De Witte\}, Ward and Guchelaar, \{Henk Jan\} and Hans Gelderblom and Cleton-Jansen, \{Anne Marie\} and Vermeulen, \{Sita H.\} and Suzanne Kaal and \{van der Graaf\}, \{Winette T.A.\} and Uta Flucke and Gidding, \{Corrie E.M.\} and Schreuder, \{Hendrik W.B.\} and \{de Bont\}, \{Eveline S.J.M.\} and Caron, \{Huib N.\} and Giovanna Gattuso and Elisabetta Schiavello and Monica Terenziani and Maura Massimino and Geoff McCowage and Sumanth Nagabushan and Anuja Limaye and Victoria Rose and Daniel Catchpoole and Jorgensen, \{Andrea L.\} and Christopher Barton and Lucy Delaney and Hawcutt, \{Daniel B.\} and Munir Pirmohamed and Barry Pizer and Coenen, \{Marieke J.H.\} and \{te Loo\}, \{D. Maroeska W.M.\}",

note = "Publisher Copyright: Copyright {\textcopyright} 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.",

year = "2023",

month = jan,

day = "9",

doi = "10.3389/fphar.2022.980309",

language = "English",

volume = "13",

journal = "Frontiers in Pharmacology",

issn = "1663-9812",

publisher = "Frontiers Media SA",

}

Hurkmans, EGE, Klumpers, MJ, Dello Russo, C, De Witte, W, Guchelaar, HJ, Gelderblom, H, Cleton-Jansen, AM, Vermeulen, SH, Kaal, S, van der Graaf, WTA, Flucke, U, Gidding, CEM, Schreuder, HWB, de Bont, ESJM, Caron, HN, Gattuso, G, Schiavello, E, Terenziani, M, Massimino, M, McCowage, G, Nagabushan, S, Limaye, A, Rose, V, Catchpoole, D, Jorgensen, AL, Barton, C, Delaney, L, Hawcutt, DB, Pirmohamed, M, Pizer, B, Coenen, MJH & te Loo, DMWM 2023, 'Genome-wide analyses of platinum-induced ototoxicity in childhood cancer patients: Results of GO-CAT and United Kingdom MAGIC consortia', Frontiers in Pharmacology, vol. 13, 980309. https://doi.org/10.3389/fphar.2022.980309

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 - https://www.scopus.com/pages/publications/85146916438

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 -

Genome-wide analyses of platinum-induced ototoxicity in childhood cancer patients: Results of GO-CAT and United Kingdom MAGIC consortia

Abstract

Bibliographical note

UN SDGs

Keywords

Access to Document

Other files and links

Fingerprint

Cite this