Development of new biomarker at the level of gene alteration in cisplatin ototoxicity

Introduction: Cisplatin (CDDP) is a chemotherapeutic agent used in the treatment of many childhood cancers. It is effective through DNA platinization. The most important side effects of this alkylating agent are nephrotoxicity, ototoxicity and neurotoxicity. CDDP ototoxicity commonly causes sensorineural, bilateral, irreversible and progressive hearing loss. CDDP-induced hearing loss is particularly important in very young children, as it leads to impaired language acquisition, difficulties in learning and psychological development, and reduced social functioning that will affect them for the rest of their lives. The aim of this study is to determine biomarkers that can enable to predict cisplatin ototoxicity in childhood cancers. Material&Method: Firstly; patients with severe hearing loss were analysed with comparative genomic hybridization for candidate mutation search. We found that the ADAM6, SIX3, GNAS, NDUFV1, H19, DEFA4, ZIM2 genes were mutant in 5 patients with severe hearing loss. In line with these data, we aimed to detect the mutation status of these 7 genes in a larger patient population of childhood cancer who take CDDP treatment. For routine checks DNAs were isolated from mononuclear cells separated from the peripheral blood of 82 patients who received or were receiving CDDcisplatin treatment. Then, RT-PCR analysis was performed for 7 genes. Patients were evaluated in terms of ototoxicity using Brock and Muenster scores along with their diagnoses, cumulative cisplatin doses. Results: Of the 82 patients included in the study; 44 were boys and 38 were girls. Diagnostic distribution of patients as follows: Neuroblastoma 42.7%, Central Nervous System Tumors 14.6%, Germ Cell Tumors 11%, Hepatoblastoma 11%, Nasopharyngeal carcinoma 6.1%, Osteosarcoma 4.9%, and other tumors 9.7%. Median cumulative CDDP dose was 400 mg/m2 (75–800 mg). 28% of all patients had hearing loss. Hearing loss rates of these patients were seen as mild hearing loss in 76.8% and severe hearing loss in 23.2%. A correlation was found between the presence of ototoxicity and amplification of the ZIM2 gene (correlation coefficient 0.461, p=0.003). ZIM2 gene amplification was correlated especially advanced patients with severe hearing loss (correlation coefficient 0.38, p=0.017). Conclusion: New biomarkers are needed to predict cisplatin ototoxicity. Our study identified ZIM2 gene as a candidate biomarker. Key words: Neuroblastoma, Cisplatin, Ototoxicity, Biomarker