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

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Date
2019-07
ICR Author
Huddart, Robert
Author
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
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Type
Journal Article
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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 ( n = 762) were dichotomized to cases (moderate/severe tinnitus; n = 154) and controls (none; n = 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 ( P = 0.007) and cumulative cisplatin dose ( P = 0.007). CisIT prevalence was not significantly greater in 400 mg/m 2 -treated TCS compared with 300 ( P = 0.41), but doses >400 mg/m 2 (median 580, range 402-828) increased risk by 2.61-fold ( P < 0.0001). CisIT cases had worse hearing at each frequency (0.25-12 kHz, P < 0.0001), and reported more vertigo (OR = 6.47; P < 0.0001) and problems hearing in a crowd (OR = 8.22; P < 0.0001) than controls. Cases reported poorer health ( P < 0.0001) and greater psychotropic medication use (OR = 2.4; P = 0.003). GWAS suggested a variant near OTOS (rs7606353, P = 2 × 10 -6 ) and OTOS eQTLs were significantly enriched independently of that SNP ( P = 0.018). OTOS 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. OTOS , expressed in the cochlear lateral wall, was implicated as protective. Future studies should investigate otoprotective targets in supporting cochlear cells.
URI
https://repository.icr.ac.uk/handle/internal/3211
DOI
https://doi.org/10.1158/1078-0432.ccr-18-3179
Collections
  • Radiotherapy and Imaging
Subject
Cell Line, Tumor
Humans
Tinnitus
Disease Susceptibility
Genetic Predisposition to Disease
Cisplatin
Antineoplastic Agents
Risk Factors
Case-Control Studies
Cell Survival
Polymorphism, Single Nucleotide
Adult
Aged
Middle Aged
Genome-Wide Association Study
Young Adult
Self Report
Ototoxicity
Research team
Clinical Academic Radiotherapy (Huddart)
Language
eng
Date accepted
2019-03-25
License start date
2019-07
Citation
Clinical cancer research : an official journal of the American Association for Cancer Research, 2019, 25 (13), pp. 4104 - 4116

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