Digestive Diseases and Sciences

, Volume 61, Issue 4, pp 1039–1050 | Cite as

A Systematic Review of Esophageal MicroRNA Markers for Diagnosis and Monitoring of Barrett’s Esophagus

  • Reema Mallick
  • Santosh K. Patnaik
  • Sachin Wani
  • Ajay Bansal
Original Article



Esophageal epithelial microRNAs may be used to diagnose Barrett’s esophagus (BE) and possibly monitor its progression to esophageal adenocarcinoma (EAC).


We reviewed studies that have investigated this to identify microRNAs with high biomarker potential for screening and disease monitoring in BE.


PubMed and EMBASE databases were searched for studies that quantified esophageal epithelial microRNAs. Publications reporting microRNA comparisons of normal, non-dysplastic BE, BE with high-grade dysplasia (HGD), and EAC tissues using both unbiased discovery and independent validation phases were reviewed.


Eleven studies on microRNA expression differences between normal epithelium and non-dysplastic BE (seven studies), HGD (4) or EAC (7), or between non-dysplastic BE and HGD (3) or EAC (6) were identified, and the findings of their validation phase were analyzed. Increased miR-192, -194, and -215, and reduced miR-203 and -205 expression in BE compared to normal was noticed by all 4–6 of the seven studies that examined these microRNAs. In heterogeneity tests of the reported fold-change values, the I 2 statistics were 7.9–17.1 % (all P < 0.05). Elevated miR-192, -194, and -215, and diminished miR-203 and -205 levels were also noted for comparisons of HGD or EAC against normal. In contrast, a consistent microRNA expression difference was absent for the comparisons of HGD or EAC against BE.


MicroRNAs miR-192, -194, -203, -205, and -215 are promising tissue biomarkers for diagnosing BE. Cross-sectional data suggest that microRNAs may have a limited role in separating BE from HGD/EAC epithelia but need further testing in longitudinal follow-up studies.


Barrett’s esophagus Esophageal adenocarcinoma Gastroesophageal reflux disease MicroRNA 



Barrett’s esophagus


Esophageal adenocarcinoma


Gastroesophageal reflux disease


High-grade dysplasia



Junior Faculty Career Development Award from the American College of Gastroenterology to A. B.

Author contributions

A. B. conceived and designed the study. All authors contributed to data collection and analysis, and approved the submitted manuscript.

Compliance with ethical standards

Conflict of interest


Supplementary material

10620_2015_3959_MOESM1_ESM.doc (56 kb)
Supplementary Table 1 PRISMA 2009 checklist (DOC 55 kb)
10620_2015_3959_MOESM2_ESM.doc (57 kb)
Supplementary Table 2 Quality assessment of the reviewed studies using REMARK criteria (DOC 57 kb)


  1. 1.
    Hur C, Miller M, Kong CY, et al. Trends in esophageal adenocarcinoma incidence and mortality. Cancer. 2013;119:1149–1158.CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    Prasad GA, Wu TT, Wigle DA, et al. Endoscopic and surgical treatment of mucosal (T1a) esophageal adenocarcinoma in Barrett’s esophagus. Gastroenterology. 2009;137:815–823.CrossRefPubMedGoogle Scholar
  3. 3.
    Shaheen NJ, Sharma P, Overholt BF, et al. Radiofrequency ablation in Barrett’s esophagus with dysplasia. N Engl J Med. 2009;360:2277–2288.CrossRefPubMedGoogle Scholar
  4. 4.
    Shaheen NJ, Hur C. Garlic, silver bullets, and surveillance upper endoscopy for Barrett’s esophagus. Gastroenterology. 2013;145:273–276.CrossRefPubMedGoogle Scholar
  5. 5.
    Spechler SJ, Souza RF. Barrett’s esophagus. N Engl J Med. 2014;371:836–845.CrossRefPubMedGoogle Scholar
  6. 6.
    Sharma P. Clinical practice. Barrett’s esophagus. N Engl J Med. 2009;361:2548–2556.CrossRefPubMedGoogle Scholar
  7. 7.
    Reid BJ. Early events during neoplastic progression in Barrett’s esophagus. Cancer Biomark. 2010;9:307–324.PubMedPubMedCentralGoogle Scholar
  8. 8.
    Prasad GA, Bansal A, Sharma P, Wang KK. Predictors of progression in Barrett’s esophagus: current knowledge and future directions. Am J Gastroenterol. 2010;105:1490–1502.CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Theisen J, Stein HJ, Dittler HJ, et al. Preoperative chemotherapy unmasks underlying Barrett’s mucosa in patients with adenocarcinoma of the distal esophagus. Surg Endosc. 2002;16:671–673.CrossRefPubMedGoogle Scholar
  10. 10.
    Ross-Innes CS, Debiram-Beecham I, O’Donovan M, et al. Evaluation of a minimally invasive cell sampling device coupled with assessment of trefoil factor 3 expression for diagnosing Barrett’s esophagus: a multi-center case–control study. PLoS Med. 2015;12:e1001780.CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Kastelein F, Biermann K, Steyerberg EW, et al. Aberrant p53 protein expression is associated with an increased risk of neoplastic progression in patients with Barrett’s oesophagus. Gut. 2013;62:1676–1683.CrossRefPubMedGoogle Scholar
  12. 12.
    Lujambio A, Lowe SW. The microcosmos of cancer. Nature. 2012;482:347–355.CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Lu J, Getz G, Miska EA, et al. MicroRNA expression profiles classify human cancers. Nature. 2005;435:834–838.CrossRefPubMedGoogle Scholar
  14. 14.
    Saito M, Shiraishi K, Matsumoto K, et al. A three-microRNA signature predicts responses to platinum-based doublet chemotherapy in patients with lung adenocarcinoma. Clin Cancer Res. 2014;20:4784–4793.CrossRefPubMedGoogle Scholar
  15. 15.
    Bansal A, Lee IH, Hong X, et al. Feasibility of microRNAs as biomarkers for Barrett’s esophagus progression: a pilot cross-sectional, phase 2 biomarker study. Am J Gastroenterol. 2011;106:1055–1063.Google Scholar
  16. 16.
    Smith CM, Michael MZ, Watson DI, et al. Impact of gastro-oesophageal reflux on microRNA expression, location and function. BMC Gastroenterol. 2013;13:4.CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Bansal A, Lee IH, Hong X, et al. Discovery and validation of Barrett’s esophagus microRNA transcriptome by next generation sequencing. PLoS ONE. 2013;8:e54240.CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Fassan M, Volinia S, Palatini J, et al. MicroRNA expression profiling in human Barrett’s carcinogenesis. Int J Cancer. 2011;129:1661–1670.Google Scholar
  19. 19.
    Fassan M, Volinia S, Palatini J, et al. MicroRNA expression profiling in the histological subtypes of Barrett’s metaplasia. Clin Transl Gastroenterol. 2013;4:e34.CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Feber A, Xi L, Luketich JD, et al. MicroRNA expression profiles of esophageal cancer. J Thorac Cardiovasc Surg. 2008;135:255–260. (discussion 260).CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Wu X, Ajani JA, Gu J, et al. MicroRNA expression signatures during malignant progression from Barrett’s esophagus to esophageal adenocarcinoma. Cancer Prev Res (Phila). 2013;6:196–205.CrossRefGoogle Scholar
  22. 22.
    Garman KS, Owzar K, Hauser ER, et al. MicroRNA expression differentiates squamous epithelium from Barrett’s esophagus and esophageal cancer. Dig Dis Sci. 2013;58:3178–3188.CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Kan T, Meltzer SJ. MicroRNAs in Barrett’s esophagus and esophageal adenocarcinoma. Curr Opin Pharmacol. 2009;9:727–732.CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Kan T, Sato F, Ito T, et al. The miR-106b-25 polycistron, activated by genomic amplification, functions as an oncogene by suppressing p21 and Bim. Gastroenterology. 2009;136:1689–1700.CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Leidner RS, Ravi L, Leahy P, et al. The microRNAs, MiR-31 and MiR-375, as candidate markers in Barrett’s esophageal carcinogenesis. Genes Chromosomes Cancer. 2012;51:473–479.CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Luzna P, Gregar J, Uberall I, Radova L, Prochazka V, Ehrmann J Jr. Changes of microRNAs-192, 196a and 203 correlate with Barrett’s esophagus diagnosis and its progression compared to normal healthy individuals. Diagn Pathol. 2011;6:114.CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Maru DM, Singh RR, Hannah C, et al. MicroRNA-196a is a potential marker of progression during Barrett’s metaplasia–dysplasia–invasive adenocarcinoma sequence in esophagus. Am J Pathol. 2009;174:1940–1948.CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Mathe EA, Nguyen GH, Bowman ED, et al. MicroRNA expression in squamous cell carcinoma and adenocarcinoma of the esophagus: associations with survival. Clin Cancer Res. 2009;15:6192–6200.CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Matsuzaki J, Suzuki H, Tsugawa H, et al. Bile acids increase levels of microRNAs 221 and 222, leading to degradation of CDX2 during esophageal carcinogenesis. Gastroenterology. 2013;145:1300–1311.CrossRefPubMedGoogle Scholar
  30. 30.
    Revilla-Nuin B, Parrilla P, Lozano JJ, et al. Predictive value of microRNAs in the progression of Barrett esophagus to adenocarcinoma in a long-term follow-up study. Ann Surg. 2013;257:886–893.CrossRefPubMedGoogle Scholar
  31. 31.
    van Baal JW, Verbeek RE, Bus P, et al. MicroRNA-145 in Barrett’s oesophagus: regulating BMP4 signalling via GATA6. Gut. 2012;62:664–675.Google Scholar
  32. 32.
    Wijnhoven BP, Hussey DJ, Watson DI, Tsykin A, Smith CM, Michael MZ. MicroRNA profiling of Barrett’s oesophagus and oesophageal adenocarcinoma. Br J Surg. 2010;97:853–861.CrossRefPubMedGoogle Scholar
  33. 33.
    Yang H, Gu J, Wang KK, et al. MicroRNA expression signatures in Barrett’s esophagus and esophageal adenocarcinoma. Clin Cancer Res. 2009;15:5744–5752.CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Saad R, Chen Z, Zhu S, et al. Deciphering the unique microRNA signature in human esophageal adenocarcinoma. PLoS ONE. 2013;8:e64463.CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    McShane LM, Altman DG, Sauerbrei W, Taube SE, Gion M, Clark GM. Reporting recommendations for tumor marker prognostic studies (REMARK). J Natl Cancer Inst. 2005;97:1180–1184.CrossRefPubMedGoogle Scholar
  36. 36.
    Altman DG, Bland JM. How to obtain the confidence interval from a P value. BMJ. 2011;343:d2090.CrossRefPubMedGoogle Scholar
  37. 37.
    Streppel MM, Pai S, Campbell NR, et al. MicroRNA 223 is upregulated in the multistep progression of Barrett’s esophagus and modulates sensitivity to chemotherapy by targeting PARP1. Clin Cancer Res. 2013;19:4067–4078.CrossRefPubMedPubMedCentralGoogle Scholar
  38. 38.
    Chen Z, Saad R, Jia P, et al. Gastric adenocarcinoma has a unique microRNA signature not present in esophageal adenocarcinoma. Cancer. 2013;119:1985–1993.CrossRefPubMedPubMedCentralGoogle Scholar
  39. 39.
    Altman DG, McShane LM, Sauerbrei W, Taube SE. Reporting Recommendations for Tumor Marker Prognostic Studies (REMARK): explanation and elaboration. PLoS Med. 2012;9:e1001216.CrossRefPubMedPubMedCentralGoogle Scholar
  40. 40.
    Pepe MS, Etzioni R, Feng Z, et al. Phases of biomarker development for early detection of cancer. J Natl Cancer Inst. 2001;93:1054–1061.CrossRefPubMedGoogle Scholar
  41. 41.
    Smith E, De Young NJ, Pavey SJ, et al. Similarity of aberrant DNA methylation in Barrett’s esophagus and esophageal adenocarcinoma. Mol Cancer. 2008;7:75.CrossRefPubMedPubMedCentralGoogle Scholar
  42. 42.
    Meyer SU, Pfaffl MW, Ulbrich SE. Normalization strategies for microRNA profiling experiments: a ‘normal’ way to a hidden layer of complexity? Biotechnol Lett. 2010;32:1777–1788.CrossRefPubMedGoogle Scholar
  43. 43.
    Slaby O, Srovnal J, Radova L, et al. Dynamic changes in microRNA expression profiles reflect progression of Barrett’s esophagus to esophageal adenocarcinoma. Carcinogenesis. 2015;36:521–527.CrossRefPubMedGoogle Scholar
  44. 44.
    Lee IH, Hong X, Mathur SC, et al. A detailed analysis of next generation sequencing reads of microRNA expression in Barrett’s esophagus: absolute versus relative quantification. BMC Res Notes. 2014;7:212.CrossRefPubMedPubMedCentralGoogle Scholar
  45. 45.
    Ozsolak F, Milos PM. RNA sequencing: advances, challenges and opportunities. Nat Rev Genet. 2011;12:87–98.CrossRefPubMedPubMedCentralGoogle Scholar
  46. 46.
    Nones K, Waddell N, Wayte N, et al. Genomic catastrophes frequently arise in esophageal adenocarcinoma and drive tumorigenesis. Nat Commun. 2014;5:5224.CrossRefPubMedPubMedCentralGoogle Scholar
  47. 47.
    Rugge M, Zaninotto G, Parente P, et al. Barrett’s esophagus and adenocarcinoma risk: the experience of the North-Eastern Italian Registry (EBRA). Ann Surg. 2012;256:788–794. (discussion 794-785).CrossRefPubMedGoogle Scholar
  48. 48.
    Sharma P, Falk GW, Weston AP, Reker D, Johnston M, Sampliner RE. Dysplasia and cancer in a large multicenter cohort of patients with Barrett’s esophagus. Clin Gastroenterol Hepatol. 2006;4:566–572.CrossRefPubMedGoogle Scholar
  49. 49.
    Reid BJ, Sanchez CA, Blount PL, Levine DS. Barrett’s esophagus: cell cycle abnormalities in advancing stages of neoplastic progression. Gastroenterology. 1993;105:119–129.PubMedGoogle Scholar
  50. 50.
    Kadri SR, Lao-Sirieix P, O’Donovan M, et al. Acceptability and accuracy of a non-endoscopic screening test for Barrett’s oesophagus in primary care: cohort study. BMJ. 2010;341:c4372.CrossRefPubMedPubMedCentralGoogle Scholar
  51. 51.
    Abrams JA, Appelman HD, Beer DG, et al. Barrett’s Esophagus Translational Research Network (BETRNet): the pivotal role of multi-institutional collaboration in esophageal adenocarcinoma research. Gastroenterology. 2014;146:1586–1590.CrossRefPubMedPubMedCentralGoogle Scholar
  52. 52.
    Chiam K, Wang T, Watson DI, et al. Circulating serum exosomal miRNAs as potential biomarkers for esophageal adenocarcinoma. J Gastrointest Surg. 2015;19:1208–1215.CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York (Outside the USA) 2015

Authors and Affiliations

  1. 1.Department of SurgeryUniversity of MinnesotaMinneapolisUSA
  2. 2.Department of Thoracic SurgeryRoswell Park Cancer InstituteBuffaloUSA
  3. 3.Department of GastroenterologyUniversity of ColoradoAuroraUSA
  4. 4.Division of Gastroenterology and HepatologyVeterans Affairs Medical CenterKansas CityUSA
  5. 5.Department of GastroenterologyUniversity of Kansas School of MedicineKansas CityUSA

Personalised recommendations