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

Clemens E, Broer L, Langer T, Uitterlinden AG, de Vries ACH, van Grotel M, Pluijm SFM, Binder H, Byrne J, Broeder EVD, Crocco M, Grabow D, Kaatsch P, Kaiser M, Kenborg L, Winther JF Rechnitzer C, Hasle H, Kepak T, van der Kooi AF, Kremer LC, Kruseova J, Kuehni CE, van der Pal H, Parfitt R, Deuster D, Matulat P, Spix C, Tillmanns A, Tissing WJE, Maier L, Am Zehnhoff-Dinnesen A, Zolk O, van den Heuvel-Eibrink MM

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.