Selection and Application of Tissue microRNAs for Nonendoscopic Diagnosis of Barrett's Esophagus.
View / Open Files
Authors
Li, Xiaodun
Kleeman, Sam
Coburn, Sally B
Fumagalli, Carlo
Perner, Juliane
Jammula, Sriganesh
Pfeiffer, Ruth M
Orzolek, Linda
Hao, Haiping
Taylor, Philip R
Miremadi, Ahmad
Galeano-Dalmau, Núria
Lao-Sirieix, Pierre
Tennyson, Maria
MacRae, Shona
Cook, Michael B
Fitzgerald, Rebecca C
Publication Date
2018-09Journal Title
Gastroenterology
ISSN
0016-5085
Publisher
Elsevier BV
Volume
155
Issue
3
Pages
771-783.e3
Language
eng
Type
Article
Physical Medium
Print-Electronic
Metadata
Show full item recordCitation
Li, X., Kleeman, S., Coburn, S. B., Fumagalli, C., Perner, J., Jammula, S., Pfeiffer, R. M., et al. (2018). Selection and Application of Tissue microRNAs for Nonendoscopic Diagnosis of Barrett's Esophagus.. Gastroenterology, 155 (3), 771-783.e3. https://doi.org/10.1053/j.gastro.2018.05.050
Abstract
BACKGROUND & 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.
Keywords
Biomarker, Diagnosis, Esophageal Adenocarcinoma, Gene Regulation, Adult, Aged, Area Under Curve, Barrett Esophagus, Biopsy, Case-Control Studies, Epigenesis, Genetic, Esophagus, Female, Gene Expression, Humans, Logistic Models, Male, MicroRNAs, Middle Aged, Multivariate Analysis, Sensitivity and Specificity
Sponsorship
Cancer Research Uk (None)
NIHR Clinical Research Network Eastern (via Cambridge University Hospitals NHS Foundation Trust (CUH)) (876523)
Medical Research Council (MC_UU_12022/2)
Cancer Research UK (C14478/A12088)
Identifiers
External DOI: https://doi.org/10.1053/j.gastro.2018.05.050
This record's URL: https://www.repository.cam.ac.uk/handle/1810/282826
Statistics
Total file downloads (since January 2020). For more information on metrics see the
IRUS guide.
Recommended or similar items
The current recommendation prototype on the Apollo Repository will be turned off on 03 February 2023. Although the pilot has been fruitful for both parties, the service provider IKVA is focusing on horizon scanning products and so the recommender service can no longer be supported. We recognise the importance of recommender services in supporting research discovery and are evaluating offerings from other service providers. If you would like to offer feedback on this decision please contact us on: support@repository.cam.ac.uk