BACKGROUND: Irreversible sensorineural hearing loss is a common side effect of platinum treatment with the potential to significantly impair the neurocognitive, social and educational development of childhood cancer survivors. 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 aim of this cross-sectional cohort study was to confirm the genetic associations in a large pan-European population and to evaluate the diagnostic accuracy of the genetic markers. METHODS: Eligibility criteria required patients to be aged less than 19 years at the start of chemotherapy, which had to include cisplatin and/or carboplatin. 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 investigated. Multinomial logistic regression was performed to model the relationship between genetic predictors and platinum ototoxicity, adjusting for clinical risk factors. Additionally, measures of the diagnostic accuracy of the genetic markers were determined. RESULTS: 900 patients were included in this study. In the multinomial logistic regression, significant unique contributions were found from SLC22A2 rs316019, the age at the start of platinum treatment, cranial radiation and the interaction term [platinum compound]∗[cumulative dose of cisplatin]. The predictive performance of the genetic markers was poor compared with the clinical risk factors. CONCLUSIONS: PanCareLIFE is the largest study of cisplatin-induced ototoxicity to date and confirmed a role for the polyspecific organic cation transporter SLC22A2. However, the predictive value of the current genetic candidate markers for clinical use is negligible, which puts the value of clinical factors for risk assessment of cisplatin-induced ototoxicity back into the foreground.

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

Danish Cancer Society Research Center Childhood Cancer Research Group Copenhagen Denmark; Department of Clinical Medicine Faculty of Health Aarhus University Aarhus Denmark

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

Department of Internal Medicine Erasmus Medical Center Rotterdam the Netherlands

Department of Neurooncology Istituto Giannina Gaslini Genova Italy

Department of Otolaryngology Head and Neck Surgery Inselspital University of Berne Switzerland

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

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

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

German Childhood Cancer Registry Institute of Medical Biostatistics Epidemiology and Informatics University Medical Center of the Johannes Gutenberg University Mainz Mainz Germany; Institute of Medical Biometry and Statistics Faculty of Medicine and Medical Center University of Freiburg Freiburg 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 Pharmacology of Natural Products and Clinical Pharmacology Ulm University Medical Center Ulm Germany

Institute of Epidemiology and Medical Biometry University of Ulm Ulm 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

Princess Máxima Center for Pediatric Oncology Utrecht the Netherlands; Department of Obstetrics and Gynecology Erasmus MC Sophia Children's Hospital the Netherlands

Princess Máxima Center for Pediatric Oncology Utrecht the Netherlands; Department of Pediatric Hematology and Oncology VU Medical Center Amsterdam the Netherlands

Princess Máxima Center for Pediatric Oncology Utrecht the Netherlands; Department of Pediatric Oncology Academic Medical Center Amsterdam Amsterdam the Netherlands

Princess Máxima Center for Pediatric Oncology Utrecht the Netherlands; Department of Pediatric Oncology Erasmus MC Sophia Children's Hospital Rotterdam the Netherlands

Princess Máxima Center for Pediatric Oncology Utrecht the Netherlands; Department of Pediatric Oncology University of Groningen University Medical Center Groningen Groningen the Netherlands

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

Citace poskytuje Crossref.org

Association of candidate pharmacogenetic markers with platinum-induced ototoxicity: PanCareLIFE dataset