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.

Audiology and Speech Pathology Department BC Children's Hospital Vancouver BC Canada

BC Children's Hospital Research Institute Vancouver BC Canada

Boyne Research Institute Drogheda Ireland

Childhood Cancer Research Group Danish Cancer Society Research Center Copenhagen Denmark

Departement of Otorhinolaryngology Erasmus Medical Center Rotterdam The Netherlands

Department of Children Hemato Oncology Motol University Hospital Prague Prague Czech Republic

Department of Clinical Medicine Faculty of Health Aarhus University and University Hospital Aarhus Denmark

Department of Internal Medicine Erasmus Medical Center Rotterdam The Netherlands

Department of Internal Medicine University Hospital of Schleswig Holstein Campus Lübeck Lübeck Germany

Department of Medical Genetics University of Alberta Edmonton AB Canada

Department of Medical Microbiology and Immunology University of Alberta Edmonton AB Canada

Department of Neurooncology IRCCS Istituto Giannina Gaslini Genova Italy

Department of Obstetrics and Gynecology Erasmus MC Sophia Children's Hospital Rotterdam The Netherlands

Department of Otorhinolaryngology Head and Neck Surgery University Hospital Utrecht Utrecht The Netherlands

Department of Pediatric and Adolescent Medicine Medical University of Graz Graz Austria

Department of Pediatric Oncology Academic Medical Center Amsterdam Amsterdam The Netherlands

Department of Pediatric Oncology and Hematology University Hospital for Children and Adolescents Lübeck Germany

Department of Pediatric Oncology Erasmus MC Sophia Children's Hospital Rotterdam The Netherlands

Department of Pediatric Oncology Hematology Immunology Stuttgart Cancer Center Olgahospital Stuttgart Germany

Department of Pediatric Oncology University of Groningen University Medical Center Groningen Groningen The Netherlands

Department of Pediatrics Aarhus University Hospital Aarhus Denmark

Department of Pediatrics and Adolescent Medicine Copenhagen University Hospital Rigshospitalet Copenhagen Denmark

Department of Phoniatrics and Pedaudiology University Hospital Münster Westphalian Wilhelm University Münster Germany

Division of Translational Therapeutics Department of Pediatrics University of British Columbia Vancouver BC Canada

Epidemiology and Biostatistics Unit and DOPO Clinic IRCCS Istituto Giannina Gaslini Genova Italy

Faculty of Pharmaceutical Sciences University of British Columbia British Columbia Canada

German Childhood Cancer Registry Institute of Medical Biostatistics Epidemiology and Informatics University Medical Center of the Johannes Gutenberg University Mainz Mainz Germany

Institute of Clinical Pharmacology Brandenburg Medical School Rüdersdorf Germany

Institute of Medical Biometry and Statistics Faculty of Medicine and Medical Center University of Freiburg Freiburg Germany

Institute of Social and Preventive Medicine University of Bern Bern Switzerland

Institute of Social Medicine and Epidemiology University of Lübeck Lübeck Germany

International Clinical Research Center Brno Czech Republic

Oncode Institute Utrecht The Netherlands

Pediatric Hematology and Oncology University Children's Hospital Bern University of Bern Bern Switzerland

Pediatric Hematology and Oncology University Children's Hospital Muenster Muenster Germany

Princess Máxima Center for Pediatric Oncology Utrecht The Netherlands

University Hospital Brno Brno Czech Republic

VU Medical Center Amsterdam The Netherlands

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