Selection and Application of Tissue microRNAs for Nonendoscopic Diagnosis of Barrett's Esophagus

Xiaodun Li, Sam Kleeman, Sally B. Coburn, Carlo Fumagalli, Juliane Perner, Sriganesh Jammula, Ruth M. Pfeiffer, Linda Orzolek, Haiping Hao, Philip R. Taylor, Ahmad Miremadi, Núria Galeano-Dalmau, Pierre Lao-Sirieix, Maria Tennyson, Shona MacRae, Michael B. Cook, Rebecca C. Fitzgerald

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)771-783.e3
JournalGastroenterology
Volume155
Issue number3
DOIs
StatePublished - Sep 1 2018

Fingerprint

Barrett Esophagus
MicroRNAs
Area Under Curve
Esophagus
Logistic Models
Epithelial Cells
Sensitivity and Specificity
Antisense Oligonucleotides
Routine Diagnostic Tests
Genetic Promoter Regions
Epigenomics
Endoscopy
Real-Time Polymerase Chain Reaction
Carcinogenesis
Plasmids

Keywords

  • Biomarker
  • Diagnosis
  • Esophageal Adenocarcinoma
  • Gene Regulation

ASJC Scopus subject areas

  • Gastroenterology

Cite this

Li, X., Kleeman, S., Coburn, S. B., Fumagalli, C., Perner, J., Jammula, S., ... Fitzgerald, R. C. (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

Selection and Application of Tissue microRNAs for Nonendoscopic Diagnosis of Barrett's Esophagus. / 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.

In: Gastroenterology, Vol. 155, No. 3, 01.09.2018, p. 771-783.e3.

Research output: Contribution to journalArticle

Li, X, Kleeman, S, Coburn, SB, Fumagalli, C, Perner, J, Jammula, S, Pfeiffer, RM, Orzolek, L, Hao, H, Taylor, PR, Miremadi, A, Galeano-Dalmau, N, Lao-Sirieix, P, Tennyson, M, MacRae, S, Cook, MB & Fitzgerald, RC 2018, 'Selection and Application of Tissue microRNAs for Nonendoscopic Diagnosis of Barrett's Esophagus', Gastroenterology, vol. 155, no. 3, pp. 771-783.e3. https://doi.org/10.1053/j.gastro.2018.05.050
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. / Selection and Application of Tissue microRNAs for Nonendoscopic Diagnosis of Barrett's Esophagus. In: Gastroenterology. 2018 ; Vol. 155, No. 3. pp. 771-783.e3.
@article{a6fa2edee85c4e23bb81adf855deabe0,
title = "Selection and Application of Tissue microRNAs for Nonendoscopic Diagnosis of Barrett's Esophagus",
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",
author = "Xiaodun Li and Sam Kleeman and Coburn, {Sally B.} and Carlo Fumagalli and Juliane Perner and Sriganesh Jammula and Pfeiffer, {Ruth M.} and Linda Orzolek and Haiping Hao and Taylor, {Philip R.} and Ahmad Miremadi and N{\'u}ria Galeano-Dalmau and Pierre Lao-Sirieix and Maria Tennyson and Shona MacRae and Cook, {Michael B.} and Fitzgerald, {Rebecca C.}",
year = "2018",
month = "9",
day = "1",
doi = "10.1053/j.gastro.2018.05.050",
language = "English (US)",
volume = "155",
pages = "771--783.e3",
journal = "Gastroenterology",
issn = "0016-5085",
publisher = "W.B. Saunders Ltd",
number = "3",

}

TY - JOUR

T1 - Selection and Application of Tissue microRNAs for Nonendoscopic Diagnosis of Barrett's Esophagus

AU - Li, Xiaodun

AU - Kleeman, Sam

AU - Coburn, Sally B.

AU - Fumagalli, Carlo

AU - Perner, Juliane

AU - Jammula, Sriganesh

AU - Pfeiffer, Ruth M.

AU - Orzolek, Linda

AU - Hao, Haiping

AU - Taylor, Philip R.

AU - Miremadi, Ahmad

AU - Galeano-Dalmau, Núria

AU - Lao-Sirieix, Pierre

AU - Tennyson, Maria

AU - MacRae, Shona

AU - Cook, Michael B.

AU - Fitzgerald, Rebecca C.

PY - 2018/9/1

Y1 - 2018/9/1

N2 - 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.

AB - 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.

KW - Biomarker

KW - Diagnosis

KW - Esophageal Adenocarcinoma

KW - Gene Regulation

UR - http://www.scopus.com/inward/record.url?scp=85052500076&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85052500076&partnerID=8YFLogxK

U2 - 10.1053/j.gastro.2018.05.050

DO - 10.1053/j.gastro.2018.05.050

M3 - Article

C2 - 29906417

AN - SCOPUS:85052500076

VL - 155

SP - 771-783.e3

JO - Gastroenterology

JF - Gastroenterology

SN - 0016-5085

IS - 3

ER -