{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T22:31:46Z","timestamp":1790289106387,"version":"4.1.0"},"reference-count":51,"publisher":"Wiley","issue":"14","license":[{"start":{"date-parts":[[2022,3,23]],"date-time":"2022-03-23T00:00:00Z","timestamp":1647993600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000054","name":"National Cancer Institute","doi-asserted-by":"publisher","award":["CA008748"],"award-info":[{"award-number":["CA008748"]}],"id":[{"id":"10.13039\/100000054","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000054","name":"National Cancer Institute","doi-asserted-by":"publisher","award":["CA157823"],"award-info":[{"award-number":["CA157823"]}],"id":[{"id":"10.13039\/100000054","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100007234","name":"University of Chicago","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100007234","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01 CA157823"],"award-info":[{"award-number":["R01 CA157823"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Cancer Medicine"],"published-print":{"date-parts":[[2022,7]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Purpose<\/jats:title><jats:p>Cisplatin is a critical component of first\u2010line chemotherapy for several cancers, but causes peripheral sensory neuropathy, hearing loss, and tinnitus. We aimed to identify comorbidities for cisplatin\u2010induced neurotoxicities among large numbers of similarly treated patients without the confounding effect of cranial radiotherapy.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Utilizing linear and logistic regression analyses on 1680 well\u2010characterized cisplatin\u2010treated testicular cancer survivors, we analyzed associations of hearing loss, tinnitus, and peripheral neuropathy with nongenetic comorbidities. Genome\u2010wide association studies and gene\u2010based analyses were performed on each phenotype.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Hearing loss, tinnitus, and peripheral neuropathy, accounting for age and cisplatin dose, were interdependent. Survivors with these neurotoxicities experienced more hypertension and poorer self\u2010reported health. In addition, hearing loss was positively associated with BMIs at clinical evaluation and nonwork\u2010related noise exposure (&gt;5\u00a0h\/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 <jats:italic>TXNRD1,<\/jats:italic> which plays a key role in redox regulation, showed borderline significance (<jats:italic>p<\/jats:italic>\u00a0=\u00a04.2\u00a0\u00d7\u00a010<jats:sup>\u22126<\/jats:sup>) in gene\u2010based analysis. rs62283056 in <jats:italic>WFS1<\/jats:italic> previously found to be significantly associated with hearing loss (<jats:italic>n<\/jats:italic>\u00a0=\u00a0511), was marginally significant in an independent replication cohort (<jats:italic>p<\/jats:italic>\u00a0=\u00a00.06; <jats:italic>n<\/jats:italic>\u00a0=\u00a0606). Gene\u2010based analyses identified significant associations between tinnitus and <jats:italic>WNT8A<\/jats:italic> (<jats:italic>p<\/jats:italic>\u00a0=\u00a02.5\u00a0\u00d7\u00a010<jats:sup>\u22126<\/jats:sup>)<jats:italic>,<\/jats:italic> encoding a signaling protein important in germ cell tumors.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>Genetics variants in <jats:italic>TXNRD1 and WNT8A<\/jats:italic> 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.<\/jats:p><\/jats:sec>","DOI":"10.1002\/cam4.4644","type":"journal-article","created":{"date-parts":[[2022,3,24]],"date-time":"2022-03-24T21:44:39Z","timestamp":1648158279000},"page":"2801-2816","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":26,"title":["Pharmacogenomics of <scp>cisplatin\u2010induced<\/scp> neurotoxicities: Hearing loss, tinnitus, and peripheral sensory neuropathy"],"prefix":"10.1002","volume":"11","author":[{"given":"Xindi","family":"Zhang","sequence":"first","affiliation":[{"name":"Department of Medicine University of Chicago  Chicago Illinois USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthew R.","family":"Trendowski","sequence":"additional","affiliation":[{"name":"Department of Medicine University of Chicago  Chicago Illinois USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emma","family":"Wilkinson","sequence":"additional","affiliation":[{"name":"Department of Medicine University of Chicago  Chicago Illinois USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mohammad","family":"Shahbazi","sequence":"additional","affiliation":[{"name":"Department of Medicine University of Chicago  Chicago Illinois USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul C.","family":"Dinh","sequence":"additional","affiliation":[{"name":"Division of Medical Oncology Indiana University  Indianapolis Indiana USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Megan M.","family":"Shuey","sequence":"additional","affiliation":[{"name":"Department of Medicine Vanderbilt University Medical Center  Nashville Tennessee USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"name":"Regeneron Genetics Center","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Darren R.","family":"Feldman","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology Memorial Sloan\u2010Kettering Cancer Center  New York New York USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert J.","family":"Hamilton","sequence":"additional","affiliation":[{"name":"Department of Surgical Oncology Princess Margaret Cancer Centre  Toronto Ontario Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David J.","family":"Vaughn","sequence":"additional","affiliation":[{"name":"Department of Medicine University of Pennsylvania  Philadelphia Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chunkit","family":"Fung","sequence":"additional","affiliation":[{"name":"J.P. Wilmot Cancer Institute University of Rochester Medical Center  Rochester New York USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christian","family":"Kollmannsberger","sequence":"additional","affiliation":[{"name":"Division of Medical Oncology University of British Columbia  Vancouver British Columbia Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert","family":"Huddart","sequence":"additional","affiliation":[{"name":"Royal Marsden Hospital  London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Neil E.","family":"Martin","sequence":"additional","affiliation":[{"name":"Department of Radiation Oncology Dana\u2010Farber Cancer Institute  Boston Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Victoria A.","family":"Sanchez","sequence":"additional","affiliation":[{"name":"Department of Otolaryngology \u2013 Head and Neck Surgery University of South Florida  Tampa Florida USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert D.","family":"Frisina","sequence":"additional","affiliation":[{"name":"Departments of Medical Engineering and Communication Sciences and Disorders, Global Center for Hearing and Speech Research University of South Florida  Tampa Florida USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lawrence H.","family":"Einhorn","sequence":"additional","affiliation":[{"name":"Division of Medical Oncology Indiana University  Indianapolis Indiana USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nancy J.","family":"Cox","sequence":"additional","affiliation":[{"name":"Department of Medicine Vanderbilt University Medical Center  Nashville Tennessee USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lois B.","family":"Travis","sequence":"additional","affiliation":[{"name":"Division of Medical Oncology Indiana University  Indianapolis Indiana USA"},{"name":"Department of Epidemiology, Fairbanks School of Public Health Indiana University  Indianapolis Indiana USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1613-097X","authenticated-orcid":false,"given":"M. Eileen","family":"Dolan","sequence":"additional","affiliation":[{"name":"Department of Medicine University of Chicago  Chicago Illinois USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2022,3,23]]},"reference":[{"key":"e_1_2_6_2_1","doi-asserted-by":"publisher","DOI":"10.3322\/caac.20107"},{"key":"e_1_2_6_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ctrv.2006.09.006"},{"key":"e_1_2_6_4_1","doi-asserted-by":"publisher","DOI":"10.1093\/annonc\/mdx360"},{"key":"e_1_2_6_5_1","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2014.56.0896"},{"key":"e_1_2_6_6_1","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-18-2244"},{"key":"e_1_2_6_7_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-019-40138-z"},{"key":"e_1_2_6_8_1","doi-asserted-by":"publisher","DOI":"10.1093\/jnci\/dju044"},{"key":"e_1_2_6_9_1","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2017.77.0735"},{"key":"e_1_2_6_10_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12885-020-06789-2"},{"key":"e_1_2_6_11_1","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2016.66.8822"},{"key":"e_1_2_6_12_1","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-16-2809"},{"key":"e_1_2_6_13_1","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-18-3179"},{"key":"e_1_2_6_14_1","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-16-3224"},{"key":"e_1_2_6_15_1","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-17-2810"},{"key":"e_1_2_6_16_1","doi-asserted-by":"publisher","DOI":"10.1007\/s11136-005-5370-6"},{"key":"e_1_2_6_17_1","doi-asserted-by":"publisher","DOI":"10.1093\/annonc\/mds329"},{"key":"e_1_2_6_18_1","doi-asserted-by":"publisher","DOI":"10.1002\/cncr.28654"},{"key":"e_1_2_6_19_1","doi-asserted-by":"publisher","DOI":"10.1038\/ng.3656"},{"key":"e_1_2_6_20_1","doi-asserted-by":"publisher","DOI":"10.1038\/ng.3679"},{"key":"e_1_2_6_21_1","doi-asserted-by":"publisher","DOI":"10.1038\/ng.3643"},{"key":"e_1_2_6_22_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(13)60142-7"},{"key":"e_1_2_6_23_1","doi-asserted-by":"publisher","DOI":"10.1007\/978-0-387-21706-2"},{"key":"e_1_2_6_24_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-017-01261-5"},{"key":"e_1_2_6_25_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pcbi.1004219"},{"key":"e_1_2_6_26_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature11003"},{"key":"e_1_2_6_27_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gks1111"},{"key":"e_1_2_6_28_1","first-page":"1129","article-title":"Comparative genomics on Wnt8a and Wnt8b genes","volume":"26","author":"Katoh M","year":"2005","journal-title":"Int J Oncol"},{"key":"e_1_2_6_29_1","first-page":"123","article-title":"Molecular cloning and characterization of human WNT8A","volume":"19","author":"Saitoh T","year":"2001","journal-title":"Int J Oncol"},{"key":"e_1_2_6_30_1","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.36953"},{"key":"e_1_2_6_31_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.mod.2012.09.009"},{"key":"e_1_2_6_32_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41592-021-01200-9"},{"key":"e_1_2_6_33_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13045-017-0471-6"},{"key":"e_1_2_6_34_1","doi-asserted-by":"publisher","DOI":"10.1002\/med.10051"},{"key":"e_1_2_6_35_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0090279"},{"key":"e_1_2_6_36_1","doi-asserted-by":"publisher","DOI":"10.1136\/jnnp.2006.092064"},{"key":"e_1_2_6_37_1","doi-asserted-by":"publisher","DOI":"10.1007\/s12070-013-0630-1"},{"key":"e_1_2_6_38_1","doi-asserted-by":"publisher","DOI":"10.3389\/fneur.2016.00171"},{"key":"e_1_2_6_39_1","doi-asserted-by":"publisher","DOI":"10.3945\/jn.111.138610"},{"key":"e_1_2_6_40_1","first-page":"143","article-title":"Low\u2010cholesterol diet and antilipid therapy in managing tinnitus and hearing loss in patients with noise\u2010induced hearing loss and hyperlipidemia","volume":"13","author":"Sutbas A","year":"2007","journal-title":"Int Tinnitus J"},{"key":"e_1_2_6_41_1","doi-asserted-by":"publisher","DOI":"10.3109\/08037051.2015.1049466"},{"key":"e_1_2_6_42_1","doi-asserted-by":"publisher","DOI":"10.1161\/01.CIR.103.1.113"},{"key":"e_1_2_6_43_1","doi-asserted-by":"publisher","DOI":"10.1080\/00016480802495438"},{"key":"e_1_2_6_44_1","unstructured":"The Health Consequences of Smoking\u201050 Years of Progress:A report of the surgeon General Atlanta (GA)2014."},{"key":"e_1_2_6_45_1","doi-asserted-by":"publisher","DOI":"10.1001\/jamanetworkopen.2019.1703"},{"key":"e_1_2_6_46_1","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-20-2682"},{"key":"e_1_2_6_47_1","unstructured":"Smoking Cessation:A report of the surgeon general Washington (DC) 2020https:\/\/www.cdc.gov\/tobacco\/data_statistics\/sgr\/2020\u2010smoking\u2010cessation\/index.html."},{"key":"e_1_2_6_48_1","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-21-1452"},{"key":"e_1_2_6_49_1","doi-asserted-by":"publisher","DOI":"10.1093\/jnci\/djp413"},{"key":"e_1_2_6_50_1","doi-asserted-by":"crossref","first-page":"iv45\u201054","DOI":"10.1093\/neuonc\/nos203","article-title":"Peripheral neuropathies from chemotherapeutics and targeted agents: diagnosis, treatment, and prevention","volume":"14","author":"Grisold W","year":"2012","journal-title":"Neuro Oncol"},{"key":"e_1_2_6_51_1","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awl356"},{"key":"e_1_2_6_52_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0959-8049(01)00381-1"}],"container-title":["Cancer Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/cam4.4644","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/cam4.4644","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/cam4.4644","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,8,23]],"date-time":"2023-08-23T13:17:22Z","timestamp":1692796642000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/cam4.4644"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,3,23]]},"references-count":51,"journal-issue":{"issue":"14","published-print":{"date-parts":[[2022,7]]}},"alternative-id":["10.1002\/cam4.4644"],"URL":"https:\/\/doi.org\/10.1002\/cam4.4644","archive":["Portico"],"relation":{},"ISSN":["2045-7634","2045-7634"],"issn-type":[{"value":"2045-7634","type":"print"},{"value":"2045-7634","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,3,23]]},"assertion":[{"value":"2021-12-02","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2022-01-19","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2022-03-23","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}