TCERG1L allelic variation is associated with cisplatin-induced hearing loss in childhood cancer, a PanCareLIFE study

A J M Meijer; F A Diepstraten; T Langer; L Broer; I K Domingo; E Clemens; A G Uitterlinden; A C H de Vries; M van Grotel; W P Vermeij; R A Ozinga; H Binder; J Byrne; E van Dulmen-den Broeder; M L Garrè; D Grabow; P Kaatsch; M Kaiser; L Kenborg; J F Winther; C Rechnitzer; H Hasle; T Kepak; K Kepakova; W J E Tissing; A L F van der Kooi; L C M Kremer; J Kruseova; S M F Pluijm; C E Kuehni; H J H van der Pal; R Parfitt; C Spix; A Tillmanns; D Deuster; P Matulat; G Calaminus; A E Hoetink; S Elsner; J Gebauer; R Haupt; H Lackner; C Blattmann; S J C M M Neggers; S R Rassekh; G E B Wright; B Brooks; A P Nagtegaal; B I Drögemöller; C J D Ross; A P Bhavsar; A G Am Zehnhoff-Dinnesen; B C Carleton; O Zolk; M M van den Heuvel-Eibrink; PanCareLIFE Consortium; and the CPNDS Consortium

doi:10.1038/s41698-021-00178-z

TCERG1L allelic variation is associated with cisplatin-induced hearing loss in childhood cancer, a PanCareLIFE study

NPJ Precis Oncol. 2021 Jul 14;5(1):64. doi: 10.1038/s41698-021-00178-z.

Authors

A J M Meijer^#¹, F A Diepstraten^#², T Langer^#³, L Broer⁴, I K Domingo⁵, E Clemens^{2

6}, A G Uitterlinden⁴, A C H de Vries^{2

6}, M van Grotel², W P Vermeij^{2

7}, R A Ozinga^{2

7}, H Binder^{8

9}, J Byrne¹⁰, E van Dulmen-den Broeder^{2

11}, M L Garrè¹², D Grabow⁸, P Kaatsch⁸, M Kaiser⁸, L Kenborg¹³, J F Winther^{13

14}, C Rechnitzer¹⁵, H Hasle¹⁶, T Kepak^{17

18}, K Kepakova^{17

18}, W J E Tissing^{2

19}, A L F van der Kooi^{2

20}, L C M Kremer^{2

21}, J Kruseova²², S M F Pluijm², C E Kuehni^{23

24}, H J H van der Pal^{2

21}, R Parfitt²⁵, C Spix⁸, A Tillmanns²⁵, D Deuster²⁵, P Matulat²⁵, G Calaminus²⁶, A E Hoetink²⁷, S Elsner²⁸, J Gebauer²⁹, R Haupt³⁰, H Lackner³¹, C Blattmann³², S J C M M Neggers^{2

4}, S R Rassekh^{33

34}, G E B Wright^{33

34}, B Brooks³⁵, A P Nagtegaal³⁶, B I Drögemöller^{33

37}, C J D Ross^{33

37}, A P Bhavsar^{5

38}, A G Am Zehnhoff-Dinnesen²⁵, B C Carleton^{33

37}, O Zolk³⁹, M M van den Heuvel-Eibrink^{2

6}; PanCareLIFE Consortium; and the CPNDS Consortium

Collaborators

A C H de Vries, M van Grotel, E van Dulmen-den Broeder, A L F van der Kooi, L C M Kremer, H J H van der Pal, G Calaminus, A E Hoetink, M M van den Heuvel-Eibrink

Affiliations

¹ Princess Máxima Center for Pediatric Oncology, Utrecht, The Netherlands. a.j.m.meijer-16@prinsesmaximacentrum.nl.
² Princess Máxima Center for Pediatric Oncology, Utrecht, The Netherlands.
³ Department of Pediatric Oncology and Hematology, University Hospital for Children and Adolescents, Lübeck, Germany.
⁴ Department of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands.
⁵ Department of Medical Microbiology and Immunology, University of Alberta, Edmonton, AB, Canada.
⁶ Department of Pediatric Oncology, Erasmus MC - Sophia Children's Hospital, Rotterdam, The Netherlands.
⁷ Oncode Institute, Utrecht, The Netherlands.
⁸ German Childhood Cancer Registry, Institute of Medical Biostatistics, Epidemiology and Informatics, University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany.
⁹ Institute of Medical Biometry and Statistics, Faculty of Medicine and Medical Center, University of Freiburg, Freiburg, Germany.
¹⁰ Boyne Research Institute, Drogheda, Ireland.
¹¹ VU Medical Center, Amsterdam, The Netherlands.
¹² Department of Neurooncology, IRCCS Istituto Giannina Gaslini, Genova, Italy.
¹³ Childhood Cancer Research Group, Danish Cancer Society Research Center, Copenhagen, Denmark.
¹⁴ Department of Clinical Medicine, Faculty of Health, Aarhus University and University Hospital, Aarhus, Denmark.
¹⁵ Department of Pediatrics and Adolescent Medicine, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark.
¹⁶ Department of Pediatrics, Aarhus University Hospital, Aarhus, Denmark.
¹⁷ University Hospital Brno, Brno, Czech Republic.
¹⁸ International Clinical Research Center (FNUSA-ICRC), Brno, Czech Republic.
¹⁹ Department of Pediatric Oncology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
²⁰ Department of Obstetrics and Gynecology, Erasmus MC - Sophia Children's Hospital, Rotterdam, The Netherlands.
²¹ Department of Pediatric Oncology, Academic Medical Center Amsterdam, Amsterdam, The Netherlands.
²² Department of Children Hemato-Oncology, Motol University Hospital Prague, Prague, Czech Republic.
²³ Institute of Social and Preventive Medicine, University of Bern, Bern, Switzerland.
²⁴ Pediatric Hematology and Oncology, University Children's Hospital Bern, University of Bern, Bern, Switzerland.
²⁵ Department of Phoniatrics and Pedaudiology, University Hospital Münster, Westphalian Wilhelm University, Münster, Germany.
²⁶ Pediatric Hematology and Oncology, University Children's Hospital Muenster, Muenster, Germany.
²⁷ Department of Otorhinolaryngology, Head and Neck Surgery, University Hospital Utrecht, Utrecht, The Netherlands.
²⁸ Institute of Social Medicine and Epidemiology, University of Lübeck, Lübeck, Germany.
²⁹ Department of Internal Medicine, University Hospital of Schleswig-Holstein, Campus Lübeck, Lübeck, Germany.
³⁰ Epidemiology and Biostatistics Unit and DOPO Clinic, IRCCS Istituto Giannina Gaslini, Genova, Italy.
³¹ Department of Pediatric and Adolescent Medicine, Medical University of Graz, Graz, Austria.
³² Department of Pediatric Oncology/Hematology/Immunology, Stuttgart Cancer Center, Olgahospital, Stuttgart, Germany.
³³ BC Children's Hospital Research Institute, Vancouver, BC, Canada.
³⁴ Division of Translational Therapeutics, Department of Pediatrics, University of British Columbia, Vancouver, BC, Canada.
³⁵ Audiology and Speech Pathology Department, BC Children's Hospital, Vancouver, BC, Canada.
³⁶ Departement of Otorhinolaryngology, Erasmus Medical Center, Rotterdam, The Netherlands.
³⁷ Faculty of Pharmaceutical Sciences, University of British Columbia, British Columbia, Canada.
³⁸ Department of Medical Genetics, University of Alberta, Edmonton, AB, Canada.
³⁹ Institute of Clinical Pharmacology, Brandenburg Medical School, Rüdersdorf, Germany.

^# Contributed equally.

Abstract

In children with cancer, the heterogeneity in ototoxicity occurrence after similar treatment suggests a role for genetic susceptibility. Using a genome-wide association study (GWAS) approach, we identified a genetic variant in TCERG1L (rs893507) to be associated with hearing loss in 390 non-cranial irradiated, cisplatin-treated children with cancer. These results were replicated in two independent, similarly treated cohorts (n = 192 and 188, respectively) (combined cohort: P = 5.3 × 10^-10, OR 3.11, 95% CI 2.2-4.5). Modulating TCERG1L expression in cultured human cells revealed significantly altered cellular responses to cisplatin-induced cytokine secretion and toxicity. These results contribute to insights into the genetic and pathophysiological basis of cisplatin-induced ototoxicity.