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

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

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Correspondence to Eva Clemens.

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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 (2019). https://doi.org/10.1038/s41397-019-0113-1

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