Format

Send to

Choose Destination
Clin Cancer Res. 2019 Jul 1;25(13):4104-4116. doi: 10.1158/1078-0432.CCR-18-3179. Epub 2019 Apr 5.

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

Author information

1
Department of Medicine, University of Chicago, Chicago, Illinois.
2
Departments of Biology and Computer Science, Loyola University Chicago, Chicago, Illinois.
3
Department of Medical Oncology, Indiana University, Indianapolis, Indiana.
4
Departments of Medical and Chemical & Biomolecular Engineering and Communication Sciences & Disorders, Global Center for Hearing and Speech Research, University of South Florida, Tampa, Florida.
5
Department of Medical Oncology, Memorial Sloan-Kettering Cancer Center, New York, New York.
6
Department of Surgical Oncology, Princess Margaret Cancer Centre, Toronto, Ontario, Canada.
7
Department of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
8
J.P. Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, New York.
9
Division of Medical Oncology, University of British Columbia, Vancouver, British Columbia, Canada.
10
RIKEN Center for Integrative Medical Science, Yokohama, Japan.
11
Clare Hall, University of Cambridge, Cambridge, United Kingdom.
12
Vanderbilt University Medical Center, Nashville, Tennessee.
13
Royal Marsden Hospital, London, United Kingdom.
14
Department of Oncology, Oslo University Hospital, Radiumhospital, Oslo, Norway.
15
Department of Medical Oncology, Indiana University, Indianapolis, Indiana. edolan@medicine.bsd.uchicago.edu lbtravis@iu.edu.
16
Department of Medicine, University of Chicago, Chicago, Illinois. edolan@medicine.bsd.uchicago.edu lbtravis@iu.edu.

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.

Supplemental Content

Full text links

Icon for HighWire
Loading ...
Support Center