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

Authors

null

Xindi Zhang

Department of Medicine, University of Chicago, Chicago, IL

Xindi Zhang , Matthew R. Trendowski , Emma Wilkinson , Darren R. Feldman , Robert James Hamilton , David J. Vaughn , Chunkit Fung , Christian K. Kollmannsberger , Robert A Huddart , Neil E. Martin , Paul C Dinh Jr., Robert D. Frisina , Lawrence H. Einhorn , M. Eileen Dolan , Lois B. Travis

Organizations

Department of Medicine, University of Chicago, Chicago, IL, Department of Medicine, The University of Chicago, Chicago, IL, Memorial Sloan Kettering Cancer Center, New York, NY, Division of Urologic Oncology, Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada, Department of Medicine, University of Pennsylvania, Philadelphia, PA, J.P. Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, NY, Division of Medical Oncology, University of British Columbia, Vancouver, BC, Canada, Institute of Cancer Research and Royal Marsden NHS Foundation Trust, Sutton, United Kingdom, Dana-Farber Cancer Institute/Brigham & Women's Hospital, Boston, MA, Indiana University School of Medicine, Indianapolis, IN, Departments of Medical Engineering and Communication Sciences and Disorders, Global Center for Hearing and Speech Research, University of South Florida, Tampa, FL, Indiana University Melvin and Bren Simon Cancer Center, Indianapolis, IN

Research Funding

U.S. National Institutes of Health
U.S. National Institutes of Health, Other Foundation

Background: Cisplatin is an essential component of first-line chemotherapy for many cancers, but causes neurotoxicity, including hearing loss (CisHL), tinnitus (CisTinn), and peripheral sensory neuropathy (CisPNeuro). However, few opportunities exist to identify risk factors and comorbidities for cisplatin-induced neurotoxicities among large numbers of homogenously treated patients without the confounding effect of cranial radiotherapy. Methods: Within a well-characterized clinical cohort of 1,680 cisplatin-treated testicular cancer survivors, linear and logistic regression analysis were utilized to analyze associations of CisHL (n = 1,258), CisTinn (n = 1,217), and CisPNeuro (n = 1,653) with non-genetic risk factors. Genome-wide association studies and gene-based analysis were performed on each phenotype. Results: Cisplatin-induced neurotoxicities (CisHL CisTinn, CisPNeuro), adjusting for age and cisplatin dose, were interdependent. Survivors with these neurotoxicities experienced more hypertension (CisTinn: OR = 2.62, p < 0.0001; CisHL: β = 0.25, p = 8.5 x10-4; CisPNeuro: OR = 1.86, p < 0.0001) and were more likely to report their health as poor (CisTinn: OR = 0.54, p < 0.0001; CisHL: β = -0.11, p < 0.0001; CisPNeuro: OR = 0.61, p < 0.0001). Persistent vertigo was significantly associated with both CisTinn (OR = 7.18, p < 0.0001) and CisPNeuro (OR = 4.29, p < 0.0001). In addition, CisTinn was significantly associated with hypercholesterolemia (OR = 1.78, p = 0.01). Importantly, gene-based association analyses identified significant associations between CisTinn and WNT8A (n = 1,037, p = 2.52x10-6), encoding a signaling protein important in germ cell tumors; and marginal significance between CisHL and TXNRD1 (n = 1,071, p = 4.21x10-6), thioredoxin reductase-1, which plays a key role in redox regulation. In silico analysis showed high expression levels of TXNRD1 were significantly correlated with cellular resistance to cisplatin in central nervous system tumor cells (Spearman Rho = 0.35, p = 0.04; R2= 0.14, p = 0.03), indicating TXNRD1 is protective for cisplatin-induced cytotoxicity. Previously, rs62283056 in WFS1 found to be significantly associated with CisHL (n = 511; subset of current population), was marginally significant in an independent replication cohort (p = 0.06; n = 606; subset of current population). Conclusions: Cisplatin-induced neurotoxicities are significantly associated with multiple clinical characteristics, including hypertension and self-reported poor health. WNT8A and TXNRD1 are notable risk factors for CisTinn and CisHL, respectively. Future studies should further investigate these genes and their potential impact on chemotherapy strategies. This study, based on the largest number of testicular cancer survivors investigated to date, highlights the clinical importance of these iatrogenic toxicities and their associated risk factors.

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Abstract Details

Meeting

2021 ASCO Annual Meeting

Session Type

Oral Abstract Session

Session Title

Symptoms and Survivorship

Track

Symptom Science and Palliative Care

Sub Track

Late and Long-Term Adverse Effects

Citation

J Clin Oncol 39, 2021 (suppl 15; abstr 12004)

DOI

10.1200/JCO.2021.39.15_suppl.12004

Abstract #

12004

Abstract Disclosures

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