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dc.contributor.authorEl Charif, Oen_US
dc.contributor.authorMapes, Ben_US
dc.contributor.authorTrendowski, MRen_US
dc.contributor.authorWheeler, HEen_US
dc.contributor.authorWing, Cen_US
dc.contributor.authorDinh, PCen_US
dc.contributor.authorFrisina, RDen_US
dc.contributor.authorFeldman, DRen_US
dc.contributor.authorHamilton, RJen_US
dc.contributor.authorVaughn, DJen_US
dc.contributor.authorFung, Cen_US
dc.contributor.authorKollmannsberger, Cen_US
dc.contributor.authorMushiroda, Ten_US
dc.contributor.authorKubo, Men_US
dc.contributor.authorGamazon, ERen_US
dc.contributor.authorCox, NJen_US
dc.contributor.authorHuddart, Ren_US
dc.contributor.authorArdeshir-Rouhani-Fard, Sen_US
dc.contributor.authorMonahan, Pen_US
dc.contributor.authorFossa, SDen_US
dc.contributor.authorEinhorn, LHen_US
dc.contributor.authorTravis, LBen_US
dc.contributor.authorDolan, MEen_US
dc.date.accessioned2019-04-30T11:09:50Z
dc.date.issued2019-07en_US
dc.identifier.citationClinical cancer research : an official journal of the American Association for Cancer Research, 2019, 25 (13), pp. 4104 - 4116en_US
dc.identifier.issn1078-0432en_US
dc.identifier.urihttps://repository.icr.ac.uk/handle/internal/3211
dc.identifier.eissn1557-3265en_US
dc.identifier.doi10.1158/1078-0432.ccr-18-3179en_US
dc.description.abstract<h4>Purpose</h4>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.<h4>Experimental design</h4>TCS (<i>n</i> = 762) were dichotomized to cases (moderate/severe tinnitus; <i>n</i> = 154) and controls (none; <i>n</i> = 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.<h4>Results</h4>Cisplatin-induced tinnitus (CisIT) significantly associated with age at diagnosis (<i>P</i> = 0.007) and cumulative cisplatin dose (<i>P</i> = 0.007). CisIT prevalence was not significantly greater in 400 mg/m<sup>2</sup>-treated TCS compared with 300 (<i>P</i> = 0.41), but doses >400 mg/m<sup>2</sup> (median 580, range 402-828) increased risk by 2.61-fold (<i>P</i> < 0.0001). CisIT cases had worse hearing at each frequency (0.25-12 kHz, <i>P</i> < 0.0001), and reported more vertigo (OR = 6.47; <i>P</i> < 0.0001) and problems hearing in a crowd (OR = 8.22; <i>P</i> < 0.0001) than controls. Cases reported poorer health (<i>P</i> < 0.0001) and greater psychotropic medication use (OR = 2.4; <i>P</i> = 0.003). GWAS suggested a variant near <i>OTOS</i> (rs7606353, <i>P</i> = 2 × 10<sup>-6</sup>) and <i>OTOS</i> eQTLs were significantly enriched independently of that SNP (<i>P</i> = 0.018). <i>OTOS</i> 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).<h4>Conclusions</h4>CisIT associated with several neuro-otological symptoms, increased use of psychotropic medication, and poorer health. <i>OTOS</i>, expressed in the cochlear lateral wall, was implicated as protective. Future studies should investigate otoprotective targets in supporting cochlear cells.en_US
dc.formatPrint-Electronicen_US
dc.format.extent4104 - 4116en_US
dc.languageengen_US
dc.language.isoengen_US
dc.rights.urihttp://www.rioxx.net/licenses/under-embargo-all-rights-reserveden_US
dc.subjectCell Line, Tumoren_US
dc.subjectHumansen_US
dc.subjectTinnitusen_US
dc.subjectDisease Susceptibilityen_US
dc.subjectGenetic Predisposition to Diseaseen_US
dc.subjectCisplatinen_US
dc.subjectAntineoplastic Agentsen_US
dc.subjectRisk Factorsen_US
dc.subjectCase-Control Studiesen_US
dc.subjectCell Survivalen_US
dc.subjectPolymorphism, Single Nucleotideen_US
dc.subjectAdulten_US
dc.subjectAgeden_US
dc.subjectMiddle Ageden_US
dc.subjectGenome-Wide Association Studyen_US
dc.subjectYoung Adulten_US
dc.subjectSelf Reporten_US
dc.subjectOtotoxicityen_US
dc.titleClinical and Genome-wide Analysis of Cisplatin-induced Tinnitus Implicates Novel Ototoxic Mechanisms.en_US
dc.typeJournal Article
dcterms.dateAccepted2019-03-25en_US
rioxxterms.versionofrecord10.1158/1078-0432.ccr-18-3179en_US
rioxxterms.licenseref.startdate2019-07en_US
rioxxterms.typeJournal Article/Reviewen_US
dc.relation.isPartOfClinical cancer research : an official journal of the American Association for Cancer Researchen_US
pubs.issue13en_US
pubs.notesNot knownen_US
pubs.organisational-group/ICR
pubs.organisational-group/ICR/Primary Group
pubs.organisational-group/ICR/Primary Group/ICR Divisions
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Radiotherapy and Imaging
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Radiotherapy and Imaging/Clinical Academic Radiotherapy (Huddart)
pubs.publication-statusPublisheden_US
pubs.volume25en_US
pubs.embargo.termsNot knownen_US
icr.researchteamClinical Academic Radiotherapy (Huddart)en_US
dc.contributor.icrauthorHuddart, Roberten_US


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