Pharmacogenomics of cisplatin‐induced neurotoxicities: Hearing loss, tinnitus, and peripheral sensory neuropathy
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...
| Asıl Yazarlar: | , , , , , , , , , , , , , , , , , , , |
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| Materyal Türü: | Makale |
| Dil: | English |
| Baskı/Yayın Bilgisi: |
Wiley
2022-07-01
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| Seri Bilgileri: | Cancer Medicine |
| Konular: | |
| Online Erişim: | https://doi.org/10.1002/cam4.4644 |
| _version_ | 1828403186246877184 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Xindi Zhang |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-10T10:14:50Z |
| format | Article |
| id | doaj.art-44f25d0b9c9c44fea27f757e2ecf0dda |
| institution | Directory Open Access Journal |
| issn | 2045-7634 |
| language | English |
| last_indexed | 2024-12-10T10:14:50Z |
| publishDate | 2022-07-01 |
| publisher | Wiley |
| record_format | Article |
| series | Cancer Medicine |
| spelling | doaj.art-44f25d0b9c9c44fea27f757e2ecf0dda2022-12-22T01:53:02ZengWileyCancer Medicine2045-76342022-07-0111142801281610.1002/cam4.4644Pharmacogenomics of cisplatin‐induced neurotoxicities: Hearing loss, tinnitus, and peripheral sensory neuropathyXindi Zhang0Matthew R. Trendowski1Emma Wilkinson2Mohammad Shahbazi3Paul C. Dinh4Megan M. Shuey5Regeneron Genetics CenterDarren R. Feldman6Robert J. Hamilton7David J. Vaughn8Chunkit Fung9Christian Kollmannsberger10Robert Huddart11Neil E. Martin12Victoria A. Sanchez13Robert D. Frisina14Lawrence H. Einhorn15Nancy J. Cox16Lois B. Travis17M. Eileen Dolan18Department of Medicine University of Chicago Chicago Illinois USADepartment of Medicine University of Chicago Chicago Illinois USADepartment of Medicine University of Chicago Chicago Illinois USADepartment of Medicine University of Chicago Chicago Illinois USADivision of Medical Oncology Indiana University Indianapolis Indiana USADepartment of Medicine Vanderbilt University Medical Center Nashville Tennessee USADepartment of Medical Oncology Memorial Sloan‐Kettering Cancer Center New York New York USADepartment of Surgical Oncology Princess Margaret Cancer Centre Toronto Ontario CanadaDepartment of Medicine University of Pennsylvania Philadelphia Pennsylvania USAJ.P. Wilmot Cancer Institute University of Rochester Medical Center Rochester New York USADivision of Medical Oncology University of British Columbia Vancouver British Columbia CanadaRoyal Marsden Hospital London UKDepartment of Radiation Oncology Dana‐Farber Cancer Institute Boston Massachusetts USADepartment of Otolaryngology – Head and Neck Surgery University of South Florida Tampa Florida USADepartments of Medical Engineering and Communication Sciences and Disorders, Global Center for Hearing and Speech Research University of South Florida Tampa Florida USADivision of Medical Oncology Indiana University Indianapolis Indiana USADepartment of Medicine Vanderbilt University Medical Center Nashville Tennessee USADivision of Medical Oncology Indiana University Indianapolis Indiana USADepartment of Medicine University of Chicago Chicago Illinois USAAbstract 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.https://doi.org/10.1002/cam4.4644cisplatinGWASototoxicitysurvivorshipneurotoxicitytesticular cancer |
| spellingShingle | 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 Pharmacogenomics of cisplatin‐induced neurotoxicities: Hearing loss, tinnitus, and peripheral sensory neuropathy Cancer Medicine cisplatin GWAS ototoxicity survivorship neurotoxicity testicular cancer |
| title | Pharmacogenomics of cisplatin‐induced neurotoxicities: Hearing loss, tinnitus, and peripheral sensory neuropathy |
| title_full | Pharmacogenomics of cisplatin‐induced neurotoxicities: Hearing loss, tinnitus, and peripheral sensory neuropathy |
| title_fullStr | Pharmacogenomics of cisplatin‐induced neurotoxicities: Hearing loss, tinnitus, and peripheral sensory neuropathy |
| title_full_unstemmed | Pharmacogenomics of cisplatin‐induced neurotoxicities: Hearing loss, tinnitus, and peripheral sensory neuropathy |
| title_short | Pharmacogenomics of cisplatin‐induced neurotoxicities: Hearing loss, tinnitus, and peripheral sensory neuropathy |
| title_sort | pharmacogenomics of cisplatin induced neurotoxicities hearing loss tinnitus and peripheral sensory neuropathy |
| topic | cisplatin GWAS ototoxicity survivorship neurotoxicity testicular cancer |
| url | https://doi.org/10.1002/cam4.4644 |
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