Ototoxicity is a common side effect of platinum treatment and manifests as irreversible, high-frequency sensorineural hearing loss. Genetic association studies have suggested a role for SNPs in genes related to the disposition of cisplatin or deafness. In this study, 429 pediatric patients that were treated with cisplatin were genotyped for 10 candidate SNPs. Logistic regression analyses revealed that younger age at treatment (≤5 years vs >15 years: OR: 9.1; 95% CI: 3.8-21.5; P = 5.6 × 10-7) and higher cumulative dose of cisplatin (>450 vs ≤300 mg/m2: OR: 2.4; 95% CI: 1.3-4.6; P = 0.007) confer a significant risk of ototoxicity. Of the SNPs investigated, none of them were significantly associated with an increase of ototoxicity. In the meta-analysis, ACYP2 rs1872328 (OR: 3.94; 95% CI: 1.04-14.03; P = 0.04) and SLC22A2 rs316019 (OR: 1.46; 95% CI: 1.07-2.00; P = 0.02) were associated with ototoxicity. In order to increase the understanding of the association between SNPs and ototoxicity, we propose a polygenic model, which takes into account multiple interacting genes of the cisplatin pathway that together confer an increased risk of ototoxicity.

Aarhus University Hospital Department of Pediatrics Aarhus University Hospital Aarhus Denmark

Boyne Research Institute Drogheda Ireland

Danish Cancer Society Research Center 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 Rotterdam The Netherlands

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 University of Groningen University Medical Center Groningen Groningen The Netherlands

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

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

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

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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