Genetic variation of cisplatin-induced ototoxicity in non-cranial-irradiated pediatric patients using a candidate gene approach: The International PanCareLIFE Study

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaperJournal articleResearchpeer-review

  • Eva Clemens, Department of Pediatric Oncology, Erasmus MC - Sophia Children's Hospital, Rotterdam, The Netherlands. e.clemens@erasmusmc.nl.
  • ,
  • Linda Broer, Department of Epidemiology, Erasmus University Medical Center, Rotterdam, The Netherlands ; Department of Internal Medicine, Genetics Laboratory, Erasmus Medical Center Rotterdam, Rotterdam, The Netherlands.
  • ,
  • Thorsten Langer, Department of Pediatric Oncology and Hematology, University Hospital for Children and Adolescents, Lübeck, Germany.
  • ,
  • André G Uitterlinden, Department of Epidemiology, Erasmus University Medical Center, Rotterdam, The Netherlands ; Department of Internal Medicine, Genetics Laboratory, Erasmus Medical Center Rotterdam, Rotterdam, The Netherlands.
  • ,
  • Andrica C H de Vries, Department of Pediatric Oncology/Hematology, Erasmus MC-Sophia Children's Hospital, Rotterdam, The Netherlands;
  • ,
  • Martine van Grotel, Princess Maxima Center for Pediatric Oncology, Utrecht, The Netherlands.
  • ,
  • Saskia F M Pluijm, Princess Maxima Center for Pediatric Oncology, Utrecht, The Netherlands.
  • ,
  • Harald Binder, Institute of Medical Biometry and Statistics, Faculty of Medicine and Medical Center, University of Freiburg, Freiburg, Germany.
  • ,
  • Julianne Byrne, Boyne Research Institute, Drogheda, Ireland.
  • ,
  • Eline van Dulmen-den Broeder, Department of Pediatric Hematology and Oncology, VU Medical Center, Amsterdam, The Netherlands.
  • ,
  • Marco Crocco, Department of Neurooncology, Istituto Giannina Gaslini, Genova, Italy.
  • ,
  • Desiree Grabow, German Childhood Cancer Registry, Institute of Medical Biostatistics, Epidemiology and Informatics, University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany.
  • ,
  • Peter Kaatsch, German Childhood Cancer Registry, Institute of Medical Biostatistics, Epidemiology and Informatics, University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany.
  • ,
  • Melanie Kaiser, German Childhood Cancer Registry, Institute of Medical Biostatistics, Epidemiology and Informatics, University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany.
  • ,
  • Line Kenborg, Danish Cancer Society Research Center, Danish Cancer Society, Copenhagen, Denmark.
  • ,
  • Jeanette F Winther
  • Catherine Rechnitzer, The Department of Pediatrics and Adolescent Medicine, Copenhagen University Hospital, Rigshospitalet, Blegdamsvej 9, 2100, Copenhagen, Denmark.
  • ,
  • Henrik Hasle
  • Tomas Kepak, Czech Republic & International Clinical Research Center (FNUSA-ICRC), University Hospital Brno, Brno, Czech Republic.
  • ,
  • Anne-Lotte F van der Kooi, Division of Reproductive Endocrinology and Infertility, Department of Obstetrics and Gynecology, Erasmus MC - Sophia Children's Hospital, Rotterdam, The Netherlands.
  • ,
  • Leontien C Kremer, Department Pediatric Oncology, Emma Children's Hospital/Academic Medical Center (AMC), Amsterdam, The Netherlands.
  • ,
  • Jarmila Kruseova, Department of Children Hemato-Oncology, Motol University Hospital Prague, Prague, Czech Republic.
  • ,
  • Claudia E Kuehni, Institute of Social and Preventive Medicine (ISPM), University of Bern, Finkenhubelweg 11, Bern, Switzerland, CH-3012.
  • ,
  • Heleen van der Pal, Department Pediatric Oncology, Emma Children's Hospital/Academic Medical Center (AMC), Amsterdam, The Netherlands.
  • ,
  • Ross Parfitt, Department of Phoniatrics and Pedaudiology, University Hospital Münster, Westphalian Wilhelm University, Münster, Germany.
  • ,
  • Dirk Deuster, Department of Phoniatrics and Pedaudiology, University Hospital Münster, Westphalian Wilhelm University, Münster, Germany.
  • ,
  • Peter Matulat, Department of Phoniatrics and Pedaudiology, University Hospital Münster, Westphalian Wilhelm University, Münster, Germany.
  • ,
  • Claudia Spix, German Childhood Cancer Registry, Institute of Medical Biostatistics, Epidemiology and Informatics, University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany.
  • ,
  • Amelie Tillmanns, Department of Phoniatrics and Pedaudiology, University Hospital Münster, Westphalian Wilhelm University, Münster, Germany.
  • ,
  • Wim J E Tissing, Department of Pediatric Oncology/Hematology, University of Groningen, Beatrix Children's Hospital, University Medical Center Groningen, Groningen, the Netherlands.
  • ,
  • Lara Maier, Institute of Pharmacology of Natural Products and Clinical Pharmacology, Ulm University Medical Center, Ulm, Germany.
  • ,
  • Antoinette Am Zehnhoff-Dinnesen, Department of Phoniatrics and Pedaudiology, University Hospital Münster, Westphalian Wilhelm University, Münster, Germany.
  • ,
  • Oliver Zolk, Institute of Pharmacology of Natural Products and Clinical Pharmacology, Ulm University Medical Center, Ulm, Germany.
  • ,
  • Marry M van den Heuvel-Eibrink, Princess Maxima Center for Pediatric Oncology, Utrecht, The Netherlands.
  • ,
  • PanCareLIFE Consortium

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.

Original languageEnglish
JournalThe Pharmacogenomics Journal
Volume20
Issue2
Pages (from-to)294-305
Number of pages12
ISSN1470-269X
DOIs
Publication statusPublished - Apr 2020

See relations at Aarhus University Citationformats

ID: 171283802