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 (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.

• Authors: Omar El Charif, Brandon Mapes, Matthew R Trendowski, Heather E Wheeler, Claudia Wing, Paul C Dinh Jr, Robert D Frisina, Darren R Feldman, Robert J Hamilton, David J Vaughn, Chunkit Fung, Christian Kollmannsberger, Taisei Mushiroda, Michiaki Kubo, Eric R Gamazon, Nancy J Cox, Robert Huddart, Shirin Ardeshir-Rouhani-Fard, Patrick Monahan, Sophie D Fossa, Lawrence H Einhorn, Lois B Travis, M Eileen Dolan
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 25 Issue 13 Pg. 4104-4116 (07 01 2019) ISSN: 1557-3265 [Electronic] United States
• PMID: 30952644 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: ©2019 American Association for Cancer Research.

Chemical References

• Antineoplastic Agents
• Cisplatin

Topics

• Adult
• Aged
• Antineoplastic Agents (adverse effects, therapeutic use)
• Case-Control Studies
• Cell Line, Tumor
• Cell Survival (genetics)
• Cisplatin (adverse effects, therapeutic use)
• Disease Susceptibility
• Genetic Predisposition to Disease
• Genome-Wide Association Study
• Humans
• Middle Aged
• Ototoxicity (diagnosis, etiology, therapy)
• Polymorphism, Single Nucleotide
• Risk Factors
• Self Report
• Tinnitus (diagnosis, etiology, therapy)
• Young Adult