Clinical and Genome-wide Analysis of Cisplatin-induced Tinnitus Implicates Novel Ototoxic Mechanisms. Journal Article

Authors: El Charif, O; Mapes, B; Trendowski, MR; Wheeler, HE; Wing, C; Dinh, PC; Frisina, RD; Feldman, DR; Hamilton, RJ; Vaughn, DJ; Fung, C; Kollmannsberger, C; Mushiroda, T; Kubo, M; Gamazon, ER; Cox, NJ; Huddart, R; Ardeshir-Rouhani-Fard, S; Monahan, P; Fossa, SD; Einhorn, LH; Travis, LB; Dolan, ME
Article Title: Clinical and Genome-wide Analysis of Cisplatin-induced Tinnitus Implicates Novel Ototoxic Mechanisms.
Abstract: PURPOSE: Cisplatin, a commonly used chemotherapeutic, results in tinnitus, the phantom perception of sound. Our purpose was to identify the clinical and genetic determinants of tinnitus among testicular cancer survivors (TCS) following cisplatin-based chemotherapy. EXPERIMENTAL DESIGN: TCS ( = 762) were dichotomized to cases (moderate/severe tinnitus; = 154) and controls (none; = 608). Logistic regression was used to evaluate associations with comorbidities and SNP dosages in genome-wide association study (GWAS) following quality control and imputation (covariates: age, noise exposure, cisplatin dose, genetic principal components). Pathway over-representation tests and functional studies in mouse auditory cells were performed. RESULTS: Cisplatin-induced tinnitus (CisIT) significantly associated with age at diagnosis ( = 0.007) and cumulative cisplatin dose ( = 0.007). CisIT prevalence was not significantly greater in 400 mg/m-treated TCS compared with 300 ( = 0.41), but doses >400 mg/m (median 580, range 402-828) increased risk by 2.61-fold ( 0.0001). CisIT cases had worse hearing at each frequency (0.25-12 kHz, 0.0001), and reported more vertigo (OR = 6.47; 0.0001) and problems hearing in a crowd (OR = 8.22; 0.0001) than controls. Cases reported poorer health ( 0.0001) and greater psychotropic medication use (OR = 2.4; = 0.003). GWAS suggested a variant near (rs7606353, = 2 × 10) and eQTLs were significantly enriched independently of that SNP ( = 0.018). overexpression in HEI-OC1, a mouse auditory cell line, resulted in resistance to cisplatin-induced cytotoxicity. Pathway analysis implicated potassium ion transport (q = 0.007). CONCLUSIONS: CisIT associated with several neuro-otological symptoms, increased use of psychotropic medication, and poorer health. , expressed in the cochlear lateral wall, was implicated as protective. Future studies should investigate otoprotective targets in supporting cochlear cells.
Journal Title: Clinical cancer research : an official journal of the American Association for Cancer Research
ISSN: 1078-0432; 1078-0432
Publisher: AACR  
Date Published: 2019