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dc.contributor.authorLi, Xiaodun
dc.contributor.authorKleeman, Sam
dc.contributor.authorCoburn, Sally B
dc.contributor.authorFumagalli, Carlo
dc.contributor.authorPerner, Juliane
dc.contributor.authorJammula, Sriganesh
dc.contributor.authorPfeiffer, Ruth M
dc.contributor.authorOrzolek, Linda
dc.contributor.authorHao, Haiping
dc.contributor.authorTaylor, Philip R
dc.contributor.authorMiremadi, Ahmad
dc.contributor.authorGaleano-Dalmau, Núria
dc.contributor.authorLao-Sirieix, Pierre
dc.contributor.authorTennyson, Maria
dc.contributor.authorMacRae, Shona
dc.contributor.authorCook, Michael B
dc.contributor.authorFitzgerald, Rebecca C
dc.date.accessioned2018-09-27T14:11:36Z
dc.date.available2018-09-27T14:11:36Z
dc.date.issued2018-09
dc.identifier.issn0016-5085
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/282826
dc.description.abstractBACKGROUND & AIMS: MicroRNA (miRNA) is highly stable in biospecimens and provides tissue-specific profiles, making it a useful biomarker of carcinogenesis. We aimed to discover a set of miRNAs that could accurately discriminate Barrett's esophagus (BE) from normal esophageal tissue and to test its diagnostic accuracy when applied to samples collected by a noninvasive esophageal cell sampling device. METHODS: We analyzed miRNA expression profiles of 2 independent sets of esophageal biopsy tissues collected during endoscopy from 38 patients with BE and 26 patients with normal esophagus (controls) using Agilent microarray and Nanostring nCounter assays. Consistently up-regulated miRNAs were quantified by real-time polymerase chain reaction in esophageal tissues collected by Cytosponge from patients with BE vs without BE. miRNAs were expressed from plasmids and antisense oligonucleotides were expressed in normal esophageal squamous cells; effects on proliferation and gene expression patterns were analyzed. RESULTS: We identified 15 miRNAs that were significantly up-regulated in BE vs control tissues. Of these, 11 (MIR215, MIR194, MIR 192, MIR196a, MIR199b, MIR10a, MIR145, MIR181a, MIR30a, MIR7, and MIR199a) were validated in Cytosponge samples. The miRNAs with the greatest increases in BE tissues (7.9-fold increase in expression or more, P < .0001: MIR196a, MIR192, MIR194, and MIR215) each identified BE vs control tissues with area under the curve (AUC) values of 0.82 or more. We developed an optimized multivariable logistic regression model, based on expression levels of 6 miRNAs (MIR7, MIR30a, MIR181a, MIR192, MIR196a, and MIR199a), that identified patients with BE with an AUC value of 0.89, 86.2% sensitivity, and 91.6% specificity. Expression level of MIR192, MIR196a, MIR199a, combined that of trefoil factor 3, identified patients with BE with an AUC of 0.93, 93.1% sensitivity, and 93.7% specificity. Hypomethylation was observed in the promoter region of the highly up-regulated cluster MIR192-MIR194. Overexpression of these miRNAs in normal esophageal squamous cells increased their proliferation, via GRHL3 and PTEN signaling. CONCLUSIONS: In analyses of miRNA expression patterns of BE vs non-BE tissues, we identified a profile that can identify Cytosponge samples from patients with BE with an AUC of 0.93. Expression of MIR194 is increased in BE samples via epigenetic mechanisms that might be involved in BE pathogenesis.
dc.format.mediumPrint-Electronic
dc.languageeng
dc.publisherElsevier BV
dc.rightsAttribution 4.0 International
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/
dc.subjectEsophagus
dc.subjectHumans
dc.subjectBarrett Esophagus
dc.subjectMicroRNAs
dc.subjectBiopsy
dc.subjectMultivariate Analysis
dc.subjectArea Under Curve
dc.subjectLogistic Models
dc.subjectSensitivity and Specificity
dc.subjectCase-Control Studies
dc.subjectGene Expression
dc.subjectEpigenesis, Genetic
dc.subjectAdult
dc.subjectAged
dc.subjectMiddle Aged
dc.subjectFemale
dc.subjectMale
dc.titleSelection and Application of Tissue microRNAs for Nonendoscopic Diagnosis of Barrett's Esophagus.
dc.typeArticle
prism.endingPage783.e3
prism.issueIdentifier3
prism.publicationDate2018
prism.publicationNameGastroenterology
prism.startingPage771
prism.volume155
dc.identifier.doi10.17863/CAM.30190
dcterms.dateAccepted2018-05-31
rioxxterms.versionofrecord10.1053/j.gastro.2018.05.050
rioxxterms.licenseref.urihttp://www.rioxx.net/licenses/all-rights-reserved
rioxxterms.licenseref.startdate2018-09
dc.contributor.orcidFitzgerald, Rebecca [0000-0002-3434-3568]
dc.identifier.eissn1528-0012
rioxxterms.typeJournal Article/Review
pubs.funder-project-idCancer Research Uk (None)
pubs.funder-project-idNIHR Clinical Research Network Eastern (via Cambridge University Hospitals NHS Foundation Trust (CUH)) (876523)
pubs.funder-project-idMedical Research Council (MC_UU_12022/2)
pubs.funder-project-idCancer Research UK (C14478/A12088)
cam.issuedOnline2018-06-12


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Attribution 4.0 International
Except where otherwise noted, this item's licence is described as Attribution 4.0 International