Pharmacogenomics of cisplatin-induced neurotoxicities: Hearing loss, tinnitus, and peripheral sensory neuropathy

Xindi Zhang; Matthew R Trendowski; Emma Wilkinson; Mohammad Shahbazi; Paul C Dinh; Megan M Shuey; Regeneron Genetics Center; Darren R Feldman; Robert J Hamilton; David J Vaughn; Chunkit Fung; Christian Kollmannsberger; Robert Huddart; Neil E Martin; Victoria A Sanchez; Robert D Frisina; Lawrence H Einhorn; Nancy J Cox; Lois B Travis; M Eileen Dolan

doi:10.1002/cam4.4644

Pharmacogenomics of cisplatin-induced neurotoxicities: Hearing loss, tinnitus, and peripheral sensory neuropathy

Cancer Med. 2022 Jul;11(14):2801-2816. doi: 10.1002/cam4.4644. Epub 2022 Mar 23.

Authors

Xindi Zhang¹, Matthew R Trendowski¹, Emma Wilkinson¹, Mohammad Shahbazi¹, Paul C Dinh², Megan M Shuey³; Regeneron Genetics Center; Darren R Feldman⁴, Robert J Hamilton⁵, David J Vaughn⁶, Chunkit Fung⁷, Christian Kollmannsberger⁸, Robert Huddart⁹, Neil E Martin¹⁰, Victoria A Sanchez¹¹, Robert D Frisina¹², Lawrence H Einhorn², Nancy J Cox³, Lois B Travis^{2

13}, M Eileen Dolan¹

Affiliations

¹ Department of Medicine, University of Chicago, Chicago, Illinois, USA.
² Division of Medical Oncology, Indiana University, Indianapolis, Indiana, USA.
³ Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
⁴ Department of Medical Oncology, Memorial Sloan-Kettering Cancer Center, New York, New York, USA.
⁵ Department of Surgical Oncology, Princess Margaret Cancer Centre, Toronto, Ontario, Canada.
⁶ Department of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
⁷ J.P. Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, New York, USA.
⁸ Division of Medical Oncology, University of British Columbia, Vancouver, British Columbia, Canada.
⁹ Royal Marsden Hospital, London, UK.
¹⁰ Department of Radiation Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
¹¹ Department of Otolaryngology - Head and Neck Surgery, University of South Florida, Tampa, Florida, USA.
¹² Departments of Medical Engineering and Communication Sciences and Disorders, Global Center for Hearing and Speech Research, University of South Florida, Tampa, Florida, USA.
¹³ Department of Epidemiology, Fairbanks School of Public Health, Indiana University, Indianapolis, Indiana, USA.

Abstract

Purpose: Cisplatin is a critical component of first-line chemotherapy for several cancers, but causes peripheral sensory neuropathy, hearing loss, and tinnitus. We aimed to identify comorbidities for cisplatin-induced neurotoxicities among large numbers of similarly treated patients without the confounding effect of cranial radiotherapy.

Methods: Utilizing linear and logistic regression analyses on 1680 well-characterized cisplatin-treated testicular cancer survivors, we analyzed associations of hearing loss, tinnitus, and peripheral neuropathy with nongenetic comorbidities. Genome-wide association studies and gene-based analyses were performed on each phenotype.

Results: Hearing loss, tinnitus, and peripheral neuropathy, accounting for age and cisplatin dose, were interdependent. Survivors with these neurotoxicities experienced more hypertension and poorer self-reported health. In addition, hearing loss was positively associated with BMIs at clinical evaluation and nonwork-related noise exposure (>5 h/week). Tinnitus was positively associated with tobacco use, hypercholesterolemia, and noise exposure. We observed positive associations between peripheral neuropathy and persistent vertigo, tobacco use, and excess alcohol consumption. Hearing loss and TXNRD1, which plays a key role in redox regulation, showed borderline significance (p = 4.2 × 10^-6 ) in gene-based analysis. rs62283056 in WFS1 previously found to be significantly associated with hearing loss (n = 511), was marginally significant in an independent replication cohort (p = 0.06; n = 606). Gene-based analyses identified significant associations between tinnitus and WNT8A (p = 2.5 × 10^-6 ), encoding a signaling protein important in germ cell tumors.

Conclusions: Genetics variants in TXNRD1 and WNT8A are notable risk factors for hearing loss and tinnitus, respectively. Future studies should investigate these genes and if replicated, identify their potential impact on preventive strategies.

Keywords: GWAS; cisplatin; neurotoxicity; ototoxicity; survivorship; testicular cancer.

Publication types

Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural

MeSH terms

Antineoplastic Agents* / adverse effects
Cisplatin / therapeutic use
Genome-Wide Association Study
Hearing Loss* / chemically induced
Hearing Loss* / genetics
Humans
Male
Neurotoxicity Syndromes*
Peripheral Nervous System Diseases* / chemically induced
Peripheral Nervous System Diseases* / genetics
Pharmacogenetics
Sensation Disorders
Testicular Neoplasms* / genetics
Tinnitus* / chemically induced
Tinnitus* / genetics

Substances

Antineoplastic Agents
Cisplatin

Abstract

Publication types

MeSH terms

Substances

Grants and funding