Genetic association studies suggest a genetic predisposition for cisplatin-induced ototoxicity. Among other candidate genes, thiopurine methyltransferase (TPMT) is considered a critical gene for susceptibility to cisplatin-induced hearing loss in a pharmacogenetic guideline. The PanCareLIFE cross-sectional cohort study evaluated the genetic associations in a large pan-European population and assessed the diagnostic accuracy of the genetic markers. 1,112 pediatric cancer survivors who had provided biomaterial for genotyping were screened for participation in the pharmacogenetic association study. 900 participants qualified for inclusion. Based on the assessment of original audiograms, patients were assigned to three phenotype categories: no, minor, and clinically relevant hearing loss. Fourteen variants in eleven candidate genes (ABCC3, OTOS, TPMT, SLC22A2, NFE2L2, SLC16A5, LRP2, GSTP1, SOD2, WFS1, and ACYP2) were genotyped. The genotype and phenotype data represent a resource for conducting meta-analyses to derive a more precise pooled estimate of the effects of genes on the risk of hearing loss due to platinum treatment.

Aarhus University Hospital Department of Pediatrics Aarhus University Hospital Aarhus Denmark

Boyne Research Institute Drogheda Ireland

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

Danish Cancer Society Research Center Childhood Cancer Research Group Copenhagen Denmark

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

Department of Clinical Medicine Faculty of Health Aarhus University Aarhus Denmark

Department of Internal Medicine Erasmus Medical Center Rotterdam The Netherlands

Department of Neurooncology Istituto Giannina Gaslini Genova Italy

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

Department of Otolaryngology Head and Neck Surgery Inselspital University of Berne

Department of Pediatric Hematology and Oncology VU Medical Center Amsterdam The Netherlands

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 Oncology and Hematology Unit University Hospital of Geneva Cansearch Research Laboratory Geneva University Switzerland

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

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

Hospital for Children and Adolescents University of Erlangen Nuremberg Erlangen Germany

Institute for Social Medicine and Epidemiology University of Lübeck Lübeck Germany

Institute of Clinical Pharmacology Immanuel Klinik Rüdersdorf Brandenburg Medical School Theodor Fontane Germany

Institute of Epidemiology and Medical Biometry University of Ulm Ulm Germany

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

Institute of Pharmacology of Natural Products and Clinical Pharmacology Ulm University Medical Center Ulm Germany

Institute of Social and Preventive Medicine University of Bern Bern Switzerland

Paediatric Oncology Dept of Paediatrics Inselspital University of Bern Switzerland

Princess Máxima Center for Pediatric Oncology Utrecht The Netherlands

University Hospital Brno Brno Czech Republic and International Clinical Research Center Brno Czech Republic

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Byrne J, Grabow D, Campbell H, O'Brien K, Bielack S, Am Zehnhoff-Dinnesen A. PanCareLIFE: The scientific basis for a European project to improve long-term care regarding fertility, ototoxicity and health-related quality of life after cancer occurring among children and adolescents. Eur. J. Cancer. 2018;103:227–237. PubMed

Winther JF, Kenborg L, Byrne J, Hjorth L, Kaatsch P, Kremer LC. Childhood cancer survivor cohorts in Europe. Acta Oncol. 2015;54:655–668. PubMed

Clemens E, Meijer AJ, Broer L, Langer T, van der Kooi AL, Uitterlinden AG. Genetic Determinants of Ototoxicity During and After Childhood Cancer Treatment: Protocol for the PanCareLIFE Study. JMIR Res. Protoc. 2019;8:e11868. PubMed PMC

Schmidt CM, Bartholomaus E, Deuster D, Heinecke A, Dinnesen AG. The "Muenster classification" of high frequency hearing loss following cisplatin chemotherapy. Hno. 2007;55:299–306. PubMed

Langer T, Clemens E, Broer L, Uitterlinden AG, de Vries A, van Grotel M. Usefulness of current candidate genetic markers to identify childhood cancer patients at risk for platinum-induced ototoxicity: results of the European PanCareLIFE cohort study. Eur J Cancer. 2020 In Press. PubMed