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.

Details

Title
TCERG1L allelic variation is associated with cisplatin-induced hearing loss in childhood cancer, a PanCareLIFE study
Author
Meijer A J M 1   VIAFID ORCID Logo  ; Diepstraten, F A 1   VIAFID ORCID Logo  ; Langer, T 2 ; Broer, L 3 ; Domingo, I K 4 ; Clemens, E 5 ; Uitterlinden, A G 3   VIAFID ORCID Logo  ; de Vries A C H 5 ; van, Grotel M 1 ; Vermeij, W P 6   VIAFID ORCID Logo  ; Ozinga R A 6 ; Binder, H 7 ; Byrne, J 8 ; van Dulmen-den Broeder E 9 ; Garrè, M L 10 ; Grabow, D 11 ; Kaatsch, P 11 ; Kaiser, M 11 ; Kenborg, L 12 ; Winther, J F 13 ; Rechnitzer, C 14 ; Hasle, H 15   VIAFID ORCID Logo  ; Kepak, T 16   VIAFID ORCID Logo  ; Kepakova, K 16 ; Tissing W J E 17 ; van der Kooi A L F 18   VIAFID ORCID Logo  ; Kremer L C M 19 ; Kruseova, J 20 ; Pluijm S M F 1 ; Kuehni, C E 21   VIAFID ORCID Logo  ; van der Pal H J H 19 ; Parfitt, R 22 ; Spix, C 11 ; Tillmanns, A 22 ; Deuster, D 22 ; Matulat, P 22 ; Calaminus, G 23 ; Hoetink, A E 24   VIAFID ORCID Logo  ; Elsner, S 25 ; Gebauer, J 26 ; Haupt, R 27 ; Lackner, H 28 ; Blattmann, C 29 ; Neggers S J C M M 30 ; Rassekh, S R 31 ; Wright G E B 31 ; Brooks, B 32 ; Nagtegaal, A P 33   VIAFID ORCID Logo  ; Drögemöller, B I 34   VIAFID ORCID Logo  ; Ross C J D 34   VIAFID ORCID Logo  ; Bhavsar, A P 35 ; am Zehnhoff-Dinnesen A G 22 ; Carleton, B C 34   VIAFID ORCID Logo  ; Zolk, O 36   VIAFID ORCID Logo  ; van den Heuvel-Eibrink M M 5   VIAFID ORCID Logo 

1  Princess Máxima Center for Pediatric Oncology, Utrecht, The Netherlands (GRID:grid.487647.e) 
2  University Hospital for Children and Adolescents, Department of Pediatric Oncology and Hematology, Lübeck, Germany (GRID:grid.411668.c) (ISNI:0000 0000 9935 6525) 
3  Erasmus Medical Center, Department of Internal Medicine, Rotterdam, The Netherlands (GRID:grid.5645.2) (ISNI:000000040459992X) 
4  University of Alberta, Department of Medical Microbiology and Immunology, Edmonton, Canada (GRID:grid.17089.37) 
5  Princess Máxima Center for Pediatric Oncology, Utrecht, The Netherlands (GRID:grid.487647.e); Erasmus MC – Sophia Children’s Hospital, Department of Pediatric Oncology, Rotterdam, The Netherlands (GRID:grid.416135.4) 
6  Princess Máxima Center for Pediatric Oncology, Utrecht, The Netherlands (GRID:grid.487647.e); Oncode Institute, Utrecht, The Netherlands (GRID:grid.499559.d) 
7  University Medical Center of the Johannes Gutenberg University Mainz, German Childhood Cancer Registry, Institute of Medical Biostatistics, Epidemiology and Informatics, Mainz, Germany (GRID:grid.410607.4); Faculty of Medicine and Medical Center, University of Freiburg, Institute of Medical Biometry and Statistics, Freiburg, Germany (GRID:grid.5963.9) 
8  Boyne Research Institute, Drogheda, Ireland (GRID:grid.427696.8) 
9  Princess Máxima Center for Pediatric Oncology, Utrecht, The Netherlands (GRID:grid.487647.e); VU Medical Center, Amsterdam, The Netherlands (GRID:grid.16872.3a) (ISNI:0000 0004 0435 165X) 
10  IRCCS Istituto Giannina Gaslini, Department of Neurooncology, Genova, Italy (GRID:grid.419504.d) (ISNI:0000 0004 1760 0109) 
11  University Medical Center of the Johannes Gutenberg University Mainz, German Childhood Cancer Registry, Institute of Medical Biostatistics, Epidemiology and Informatics, Mainz, Germany (GRID:grid.410607.4) 
12  Danish Cancer Society Research Center, Childhood Cancer Research Group, Copenhagen, Denmark (GRID:grid.417390.8) (ISNI:0000 0001 2175 6024) 
13  Danish Cancer Society Research Center, Childhood Cancer Research Group, Copenhagen, Denmark (GRID:grid.417390.8) (ISNI:0000 0001 2175 6024); Aarhus University and University Hospital, Department of Clinical Medicine, Faculty of Health, Aarhus, Denmark (GRID:grid.7048.b) (ISNI:0000 0001 1956 2722) 
14  Department of Pediatrics and Adolescent Medicine, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark (GRID:grid.475435.4) 
15  Aarhus University Hospital, Department of Pediatrics, Aarhus, Denmark (GRID:grid.154185.c) (ISNI:0000 0004 0512 597X) 
16  University Hospital Brno, Brno, Czech Republic (GRID:grid.412554.3) (ISNI:0000 0004 0609 2751); International Clinical Research Center (FNUSA-ICRC), Brno, Czech Republic (GRID:grid.412752.7) (ISNI:0000 0004 0608 7557) 
17  Princess Máxima Center for Pediatric Oncology, Utrecht, The Netherlands (GRID:grid.487647.e); University of Groningen, University Medical Center Groningen, Department of Pediatric Oncology, Groningen, The Netherlands (GRID:grid.4494.d) (ISNI:0000 0000 9558 4598) 
18  Princess Máxima Center for Pediatric Oncology, Utrecht, The Netherlands (GRID:grid.487647.e); Erasmus MC – Sophia Children’s Hospital, Department of Obstetrics and Gynecology, Rotterdam, The Netherlands (GRID:grid.416135.4) 
19  Princess Máxima Center for Pediatric Oncology, Utrecht, The Netherlands (GRID:grid.487647.e); Academic Medical Center Amsterdam, Department of Pediatric Oncology, Amsterdam, The Netherlands (GRID:grid.5650.6) (ISNI:0000000404654431) 
20  Motol University Hospital Prague, Department of Children Hemato-Oncology, Prague, Czech Republic (GRID:grid.412826.b) (ISNI:0000 0004 0611 0905) 
21  University of Bern, Institute of Social and Preventive Medicine, Bern, Switzerland (GRID:grid.5734.5) (ISNI:0000 0001 0726 5157); University Children’s Hospital Bern, University of Bern, Pediatric Hematology and Oncology, Bern, Switzerland (GRID:grid.5734.5) (ISNI:0000 0001 0726 5157) 
22  University Hospital Münster, Westphalian Wilhelm University, Department of Phoniatrics and Pedaudiology, Münster, Germany (GRID:grid.16149.3b) (ISNI:0000 0004 0551 4246) 
23  University Children’s Hospital Muenster, Pediatric Hematology and Oncology, Muenster, Germany (GRID:grid.16149.3b) (ISNI:0000 0004 0551 4246) 
24  University Hospital Utrecht, Department of Otorhinolaryngology, Head and Neck Surgery, Utrecht, The Netherlands (GRID:grid.7692.a) (ISNI:0000000090126352) 
25  University of Lübeck, Institute of Social Medicine and Epidemiology, Lübeck, Germany (GRID:grid.4562.5) (ISNI:0000 0001 0057 2672) 
26  University Hospital of Schleswig-Holstein, Campus Lübeck, Department of Internal Medicine, Lübeck, Germany (GRID:grid.412468.d) (ISNI:0000 0004 0646 2097) 
27  IRCCS Istituto Giannina Gaslini, Epidemiology and Biostatistics Unit and DOPO Clinic, Genova, Italy (GRID:grid.419504.d) (ISNI:0000 0004 1760 0109) 
28  Medical University of Graz, Department of Pediatric and Adolescent Medicine, Graz, Austria (GRID:grid.11598.34) (ISNI:0000 0000 8988 2476) 
29  Stuttgart Cancer Center, Olgahospital, Department of Pediatric Oncology/Hematology/Immunology, Stuttgart, Germany (GRID:grid.459687.1) (ISNI:0000 0004 0493 3975) 
30  Princess Máxima Center for Pediatric Oncology, Utrecht, The Netherlands (GRID:grid.487647.e); Erasmus Medical Center, Department of Internal Medicine, Rotterdam, The Netherlands (GRID:grid.5645.2) (ISNI:000000040459992X) 
31  BC Children’s Hospital Research Institute, Vancouver, Canada (GRID:grid.414137.4) (ISNI:0000 0001 0684 7788); University of British Columbia, Division of Translational Therapeutics, Department of Pediatrics, Vancouver, Canada (GRID:grid.17091.3e) (ISNI:0000 0001 2288 9830) 
32  BC Children’s Hospital, Audiology and Speech Pathology Department, Vancouver, Canada (GRID:grid.414137.4) (ISNI:0000 0001 0684 7788) 
33  Erasmus Medical Center, Departement of Otorhinolaryngology, Rotterdam, The Netherlands (GRID:grid.5645.2) (ISNI:000000040459992X) 
34  BC Children’s Hospital Research Institute, Vancouver, Canada (GRID:grid.414137.4) (ISNI:0000 0001 0684 7788); University of British Columbia, Faculty of Pharmaceutical Sciences, British Columbia, Canada (GRID:grid.17091.3e) (ISNI:0000 0001 2288 9830) 
35  University of Alberta, Department of Medical Microbiology and Immunology, Edmonton, Canada (GRID:grid.17089.37); University of Alberta, Department of Medical Genetics, Edmonton, Canada (GRID:grid.17089.37) 
36  Brandenburg Medical School, Institute of Clinical Pharmacology, Rüdersdorf, Germany (GRID:grid.473452.3) 
Publication year
2021
Publication date
2021
Publisher
Nature Publishing Group
ISSN
2397768X
Source type
Scholarly Journal
Language of publication
English
DOI
https://doi.org/10.1038/s41698-021-00178-z
ProQuest document ID
2551409734
Copyright
© The Author(s) 2021. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.