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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.doi10.1158/1078-0432.ccr-18-3179en_US
dc.description.abstractPURPOSE: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. EXPERIMENTAL DESIGN:TCS (n = 762) were dichotomized to cases (moderate/severe tinnitus; n = 154) and controls (none; n = 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. RESULTS:Cisplatin-induced tinnitus (CisIT) significantly associated with age at diagnosis (P = 0.007) and cumulative cisplatin dose (P = 0.007). CisIT prevalence was not significantly greater in 400 mg/m2-treated TCS compared with 300 (P = 0.41), but doses >400 mg/m2 (median 580, range 402-828) increased risk by 2.61-fold (P < 0.0001). CisIT cases had worse hearing at each frequency (0.25-12 kHz, P < 0.0001), and reported more vertigo (OR = 6.47; P < 0.0001) and problems hearing in a crowd (OR = 8.22; P < 0.0001) than controls. Cases reported poorer health (P < 0.0001) and greater psychotropic medication use (OR = 2.4; P = 0.003). GWAS suggested a variant near OTOS (rs7606353, P = 2 × 10-6) and OTOS eQTLs were significantly enriched independently of that SNP (P = 0.018). OTOS 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). CONCLUSIONS:CisIT associated with several neuro-otological symptoms, increased use of psychotropic medication, and poorer health. OTOS, 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.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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