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

The Pharmacogenomics Journal volume 20, pages 294–305 (2020)Cite this article

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Abstract

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.

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Funding

This work was supported by the PanCareLIFE project that has received funding from the European Union’s Seventh Framework Programme for research, technological development and demonstration under grant agreement no. 602030. AdV received funding from the Pediatric Oncology Center Society for Research (KOCR), Rotterdam, the Netherlands. JFW received supplementary funding from the Danish Childhood Cancer Foundation and Soroptimist International Helsingør, Denmark. CEK was funded by the Swiss Cancer Research (grant no.: 4157-02-2017), the Swiss Cancer League (grant no.: 3412-02-2014), the Bernese Cancer League and the Lung League Bern.

On behalf of the PanCareLIFE consortium

P. Kaatsch22, D. Grabow22, J. Byrne23, H. Campbell23, K. O’Brien24, L. C. M. Kremer25, T. Langer26, E. van Dulmen-den Broeder27, M. H. van den Berg27, M. M. van den Heuvel-Eibrink28, A. Borgmann-Staudt29, A. am Zehnhoff-Dinnesen30, C. E. Kuehni31, R. Haupt32, T. Kepak33, C. Berger34, J. F. Winther35, J. Kruseova36, G. Calaminus37, K. Baust37, U. Dirksen38

Author information

Author notes

  1. These authors contributed equally: Eva Clemens, Linda Broer, Thorsten Langer

  2. These authors jointly supervised this work: Antoinette am Zehnhoff-Dinnesen, Oliver Zolk, Marry M. van den Heuvel-Eibrink

Authors and Affiliations

  1. Princess Máxima Center for Pediatric Oncology, Utrecht, The Netherlands

    Eva Clemens, Andrica C. H. de Vries, Martine van Grotel, Saskia F. M. Pluijm, Eline van Dulmen-den Broeder, Anne-Lotte F. van der Kooi, Leontien C. Kremer, Heleen van der Pal, Wim J. E. Tissing & Marry M. van den Heuvel-Eibrink

  2. Department of Pediatric Oncology, Erasmus MC – Sophia Children’s Hospital, Rotterdam, The Netherlands

    Eva Clemens & Andrica C. H. de Vries

  3. Department of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands

    Linda Broer & André G. Uitterlinden

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

    Thorsten Langer

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

    Harald Binder, Desiree Grabow, Peter Kaatsch, Melanie Kaiser & Claudia Spix

  6. Institute of Medical Biometry and Statistics, Faculty of Medicine and Medical Center – University of Freiburg, Freiburg, Germany

    Harald Binder

  7. Boyne Research Institute, Drogheda, Ireland

    Julianne Byrne

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

    Eline van Dulmen-den Broeder

  9. Department of Neurooncology, Istituto Giannina Gaslini, Genova, Italy

    Marco Crocco

  10. Danish Cancer Society Research Center, Copenhagen, Denmark

    Line Kenborg & Jeanette F. Winther

  11. Department of Clinical Medicine, Faculty of Health, Aarhus University, Aarhus, Denmark

    Jeanette F. Winther

  12. Department of Pediatrics and Adolescent Medicine, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark

    Catherine Rechnitzer

  13. Aarhus University Hospital, Department of Pediatrics, Aarhus University Hospital, Aarhus, Denmark

    Henrik Hasle

  14. University Hospital Brno, Brno, Czech Republic, & International Clinical Research Center (FNUSA-ICRC), Brno, Czech Republic

    Tomas Kepak

  15. Department of Obstetrics and Gynecology, Erasmus MC – Sophia Children’s Hospital, Rotterdam, The Netherlands

    Anne-Lotte F. van der Kooi

  16. Department of Pediatric Oncology, Academic Medical Center Amsterdam, Amsterdam, The Netherlands

    Leontien C. Kremer & Heleen van der Pal

  17. Department of Children Hemato-Oncology, Motol University Hospital Prague, Prague, Czech Republic

    Jarmila Kruseova

  18. Institute of Social and Preventive Medicine, University of Bern, Bern, Switzerland

    Claudia E. Kuehni

  19. Department of Phoniatrics and Pedaudiology, University Hospital Münster, Westphalian Wilhelm University, Münster, Germany

    Ross Parfitt, Dirk Deuster, Peter Matulat, Amelie Tillmanns & Antoinette am Zehnhoff-Dinnesen

  20. Department of Pediatric Oncology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands

    Wim J. E. Tissing

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

    Lara Maier & Oliver Zolk

  22. Universitätsmedizin der Johannes Gutenberg-Universität Mainz, Mainz, Germany

    P. Kaatsch & D. Grabow

  23. Boyne Research Institute, Drogheda, Ireland

    J. Byrne & H. Campbell

  24. Pintail Ltd, Dublin, Ireland

    K. O’Brien

  25. Academisch Medisch Centrum bij de Universiteitvan Amsterdam, Amsterdam, Netherlands

    L. C. M. Kremer

  26. Universität zu Lübeck, Lübeck, Germany

    T. Langer

  27. Stichting VU-VUMC, Amsterdam, Netherlands

    E. van Dulmen-den Broeder & M. H. van den Berg

  28. Erasmus Universitair Medisch Centrum Rotterdam, Rotterdam, Netherlands

    M. M. van den Heuvel-Eibrink

  29. Charité –Universitätsmedizin Berlin, Berlin, Germany

    A. Borgmann-Staudt

  30. Westfälische Wilhelms-Universität Münster, Münster, Germany

    A. am Zehnhoff-Dinnesen

  31. Universität Bern, Bern, Switzerland

    C. E. Kuehni

  32. Istituto Giannina Gaslini, Genoa, Italy

    R. Haupt

  33. Fakultni Nemocnice Brno, Brno, Czech Republic

    T. Kepak

  34. Centre Hospitalier Universitaire Saint Etienne – CHU, St. Etienne, France

    C. Berger

  35. Kraeftens Bekaempelse, Copenhagen, Denmark

    J. F. Winther

  36. Fakultni Nemocnice v Motole, Prague, Czech Republic

    J. Kruseova

  37. Universitaetsklinikum Bonn, Bonn, Germany

    G. Calaminus & K. Baust

  38. University Hospital Essen, Essen, Germany

    U. Dirksen

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  1. Eva Clemens
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  2. Linda Broer
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  16. Jeanette F. Winther
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  34. Marry M. van den Heuvel-Eibrink
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Consortia

on behalf of the PanCareLIFE consortium

  • P. Kaatsch
  • , D. Grabow
  • , J. Byrne
  • , H. Campbell
  • , K. O’Brien
  • , L. C. M. Kremer
  • , T. Langer
  • , E. van Dulmen-den Broeder
  • , M. H. van den Berg
  • , M. M. van den Heuvel-Eibrink
  • , A. Borgmann-Staudt
  • , A. am Zehnhoff-Dinnesen
  • , C. E. Kuehni
  • , R. Haupt
  • , T. Kepak
  • , C. Berger
  • , J. F. Winther
  • , J. Kruseova
  • , G. Calaminus
  • , K. Baust
  •  & U. Dirksen

Corresponding author

Correspondence to Eva Clemens.

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The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the paper. The authors declare that they have no conflict of interest.

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Members of the PanCareLIFE consortium are listed at the end of the paper

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Clemens, E., Broer, L., Langer, T. et al. Genetic variation of cisplatin-induced ototoxicity in non-cranial-irradiated pediatric patients using a candidate gene approach: The International PanCareLIFE Study. Pharmacogenomics J 20, 294–305 (2020). https://doi.org/10.1038/s41397-019-0113-1

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