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

Omar El Charif¹, Brandon Mapes¹, Matthew R Trendowski¹

¹Department of Medicine, University of Chicago, Chicago, Illinois.

Clinical Cancer Research : an Official Journal of the American Association for Cancer Research

|April 7, 2019

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/m²-treated TCS compared with 300 (P = 0.41), but doses >400 mg/m² (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.

Insights

Cisplatin chemotherapy can cause tinnitus in testicular cancer survivors. Higher doses and older age increase risk, while the gene OTOS may offer protection against this side effect.

Area of Science:

Otolaryngology
Medical Genetics
Oncology

Background:

Cisplatin is a vital chemotherapeutic agent for testicular cancer.
Tinnitus, a phantom sound perception, is a common and debilitating side effect of cisplatin treatment.
Identifying factors contributing to cisplatin-induced tinnitus (CisIT) is crucial for patient management.

Purpose of the Study:

To determine the clinical and genetic factors associated with tinnitus in testicular cancer survivors (TCS) treated with cisplatin.
To investigate the role of genetic variants and auditory cell function in CisIT.

Main Methods:

A cohort of 762 TCS was analyzed, dichotomized into cases (moderate/severe tinnitus) and controls.
Logistic regression and genome-wide association studies (GWAS) were employed to identify risk factors, including comorbidities and single nucleotide polymorphisms (SNPs).
Functional studies in mouse auditory cells and pathway analysis were conducted to explore underlying mechanisms.

Main Results:

CisIT risk significantly correlated with older age at diagnosis and cumulative cisplatin dose, with doses over 400 mg/m² increasing risk substantially.
Cases reported worse hearing, increased vertigo, and greater difficulty hearing in crowds compared to controls.
GWAS identified a potential protective variant near the OTOS gene, and its overexpression in auditory cells conferred resistance to cisplatin toxicity.

Conclusions:

CisIT is linked to neuro-otological symptoms, increased psychotropic medication use, and poorer overall health.
The gene OTOS, expressed in the cochlea, appears to play a protective role against CisIT.
Further research into otoprotective strategies targeting cochlear supporting cells is warranted.

Read full analysis

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