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

Abstract

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. TCS (<i>n</i> = 762) were dichotomized to cases (moderate/severe tinnitus; <i>n</i> = 154) and controls (none; <i>n</i> = 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. Cisplatin-induced tinnitus (CisIT) significantly associated with age at diagnosis (<i>P</i> = 0.007) and cumulative cisplatin dose (<i>P</i> = 0.007). CisIT prevalence was not significantly greater in 400 mg/m²-treated TCS compared with 300 (<i>P</i> = 0.41), but doses >400 mg/m² (median 580, range 402-828) increased risk by 2.61-fold (<i>P</i> < 0.0001). CisIT cases had worse hearing at each frequency (0.25-12 kHz, <i>P</i> < 0.0001), and reported more vertigo (OR = 6.47; <i>P</i> < 0.0001) and problems hearing in a crowd (OR = 8.22; <i>P</i> < 0.0001) than controls. Cases reported poorer health (<i>P</i> < 0.0001) and greater psychotropic medication use (OR = 2.4; <i>P</i> = 0.003). GWAS suggested a variant near <i>OTOS</i> (rs7606353, <i>P</i> = 2 × 10^-6) and <i>OTOS</i> eQTLs were significantly enriched independently of that SNP (<i>P</i> = 0.018). <i>OTOS</i> 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). CisIT associated with several neuro-otological symptoms, increased use of psychotropic medication, and poorer health. <i>OTOS</i>, expressed in the cochlear lateral wall, was implicated as protective. Future studies should investigate otoprotective targets in supporting cochlear cells.