Determination of a New Biomarker at the Level of Gene Alteration in Cisplatin Ototoxicity

Abstract

Cisplatin is an alkylating chemotherapeutic drug used in the treatment of many pediatric solid tumors, and cisplatin ototoxicity is characterized by sensorineural, bilateral, irreversible, and progressive hearing loss. The aim of this study is to identify biomarkers that may serve as predictors of cisplatin-induced ototoxicity in pediatric cancers. In our preliminary study, patients with severe hearing loss were analyzed using the comparative genomic hybridization (CGH) method. Mutations were identified in the following genes: ADAM6, SIX3, GNAS, NDUFV1, H19, DEFA4, and ZIM2. Based on these data, we aimed to investigate the mutation status of these candidate genes in a larger population of pediatric cancer patients treated with cisplatin. DNA samples were extracted from the mononuclear cells of peripheral blood samples obtained from 82 patients. These genes were analyzed using the RT-PCR technique, and ototoxicity was assessed using the Brock and Muenster classifications. Hearing loss was detected in 28% of patients; 76.8% and 23.2% had mild and severe hearing loss, respectively. A significant correlation was found between ZIM2 gene amplification and the presence of ototoxicity (rho = 0.461, p = 0.003), especially in advanced-stage cancer patients with severe hearing loss (rho = 0.38, p = 0.017). Our findings suggest that ZIM2 is a promising biomarker for predicting cisplatin ototoxicity.