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A microRNA Signature Identifies Patients at Risk of Barrett Esophagus Progression to Dysplasia and Cancer

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Abstract

Background

Progression of Barrett esophagus (BE) to esophageal adenocarcinoma occurs among a minority of BE patients. To date, BE behavior cannot be predicted on the basis of histologic features.

Aims

We compared BE samples that did not develop dysplasia or carcinoma upon follow-up of ≥ 7 years (BE nonprogressed [BEN]) with BE samples that developed carcinoma upon follow-up of 3 to 4 years (BE progressed [BEP]).

Methods

The NanoString nCounter miRNA assay was used to profile 24 biopsy samples of BE, including 13 BENs and 11 BEPs. Fifteen samples were randomly selected for miRNA prediction model training; nine were randomly selected for miRNA validation.

Results

Unpaired t tests with Welch’s correction were performed on 800 measured miRNAs to identify the most differentially expressed miRNAs for cases of BEN and BEP. The top 12 miRNAs (P < .003) were selected for principal component analyses: miR-1278, miR-1301, miR-1304-5p, miR-517b-3p, miR-584-5p, miR-599, miR-103a-3p, miR-1197, miR-1256, miR-509–3-5p, miR-544b, miR-802. The 12-miRNA signature was first self-validated on the training dataset, resulting in 7 out of the 7 BEP samples being classified as BEP (100% sensitivity) and 7 out of the 8 BEN samples being classified as BEN (87.5% specificity). Upon validation, 4 out of the 4 BEP samples were classified as BEP (100% sensitivity) and 4 out of the 5 BEN samples were classified as BEN (80% specificity). Twenty-four samples were evaluated, and 22 cases were correctly classified. Overall accuracy was 91.67%.

Conclusion

Using miRNA profiling, we have identified a 12-miRNA signature able to reliably differentiate cases of BEN from BEP.

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Abbreviations

BE:

Barrett esophagus

BEN:

Barrett esophagus nonprogressed

BEP:

Barrett esophagus progressed

EAC:

Esophageal adenocarcinoma

FFPE:

Formalin-fixed paraffin-embedded

GERD:

Gastroesophageal reflux disease

HGD:

High-grade dysplasia

MCC:

H. Lee Moffitt Cancer Center and Research Institute

miRNA:

microRNA

PC1:

First principal component

References

  1. Lin JJ, Kennedy E, Sequist LVet al. Clinical Activity of Alectinib in Advanced RET-Rearranged Non-Small-Cell Lung Cancer Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer. 2016.

  2. Martinucci I, de Bortoli N, Russo Set al. Barrett's esophagus in 2016: From pathophysiology to treatment World J Gastrointest Pharmacol Therapeut. 2016;7:190–206.

  3. Naini BV, Souza RF, Odze RD. Barrett’s esophagus: a comprehensive and contemporary review for pathologists. Am J Surg Pathol. 2016;40:e45-66

    PubMed  PubMed Central  Google Scholar 

  4. Rubenstein JH, Mattek N, Eisen G. Age- and sex-specific yield of Barrett’s esophagus by endoscopy indication. Gastrointest Endosc. 2010;71:21–27

    PubMed  Google Scholar 

  5. Malfertheiner P, Nocon M, Vieth M et al. Evolution of gastro-oesophageal reflux disease over 5 years under routine medical care–the ProGERD study. Aliment Pharmacol Therapeut. 2012;35:154–164

    CAS  Google Scholar 

  6. Bhat S, Coleman HG, Yousef F et al. Risk of malignant progression in Barrett’s esophagus patients: results from a large population-based study. J Natl Cancer Inst. 2011;103:1049–1057

    PubMed  PubMed Central  Google Scholar 

  7. Fleischer DE, Odze R, Overholt BF et al. The case for endoscopic treatment of non-dysplastic and low-grade dysplastic Barrett’s esophagus. Digest Dis Sci. 2010;55:1918–1931. https://doi.org/10.1007/s10620-010-1218-1.pdf

    Article  PubMed  Google Scholar 

  8. Wolf WA, Pasricha S, Cotton C et al. Incidence of esophageal adenocarcinoma and causes of mortality after radiofrequency ablation of barrett’s esophagus. Gastroenterology. 2015;149:e1751

    Google Scholar 

  9. Sampliner RE. Practice guidelines on the diagnosis, surveillance, and therapy of Barrett’s esophagus. The practice parameters committee of the american college of gastroenterology. Am J Gastroenterol. 1998;93:1028–1032

    CAS  PubMed  Google Scholar 

  10. Shaheen NJ, Richter JE. Barrett’s oesophagus. Lancet (London, England). 2009;373:850–861

    CAS  Google Scholar 

  11. Hvid-Jensen F, Pedersen L, Drewes AM, Sorensen HT, Funch-Jensen P. Incidence of adenocarcinoma among patients with Barrett’s esophagus. N Engl J Med. 2011;365:1375–1383

    CAS  PubMed  Google Scholar 

  12. Shaheen NJ, Falk GW, Iyer PG, Gerson LB. ACG clinical guideline: diagnosis and management of barrett’s esophagus. Am J Gastroenterol. 2016;111:51

    Google Scholar 

  13. van der Burgh A, Dees J, Hop WC, van Blankenstein M. Oesophageal cancer is an uncommon cause of death in patients with Barrett’s oesophagus. Gut. 1996;39:5–8

    PubMed  PubMed Central  Google Scholar 

  14. Macdonald CE, Wicks AC, Playford RJ. Final results from 10 year cohort of patients undergoing surveillance for Barrett’s oesophagus: observational study. BMJ Clin Res. 2000;321:1252–1255

    CAS  Google Scholar 

  15. Curvers WL, Peters FP, Elzer B et al. Quality of Barrett’s surveillance in The Netherlands: a standardized review of endoscopy and pathology reports. Eur J Gastroenterol Hepatol. 2008;20:601–607

    PubMed  Google Scholar 

  16. Boyce HW. Barrett esophagus: endoscopic findings and what to biopsy. J Clin Gastroenterol. 2003;36:S6–S18 ((discussion S26–18)).

    PubMed  Google Scholar 

  17. Fitzgerald RC, di Pietro M, Ragunath K et al. British Society of Gastroenterology guidelines on the diagnosis and management of Barrett’s oesophagus. Gut. 2014;63:7–42

    PubMed  Google Scholar 

  18. Inadomi JM, Sampliner R, Lagergren J, Lieberman D, Fendrick AM, Vakil N. Screening and surveillance for Barrett esophagus in high-risk groups: a cost-utility analysis. Ann Internal Med. 2003;138:176–186

    Google Scholar 

  19. de Jonge PJ, van Blankenstein M, Looman CW, Casparie MK, Meijer GA, Kuipers EJ. Risk of malignant progression in patients with Barrett’s oesophagus: a Dutch nationwide cohort study. Gut. 2010;59:1030–1036

    PubMed  Google Scholar 

  20. Bartel DP. MicroRNAs: genomics, biogenesis, mechanism, and function. Cell. 2004;116:281–297

    CAS  PubMed  Google Scholar 

  21. Croce CM. Causes and consequences of microRNA dysregulation in cancer. Nat Rev Genet. 2009;10:704

    CAS  PubMed  PubMed Central  Google Scholar 

  22. Smith CM, Watson DI, Michael MZ, Hussey DJ. MicroRNAs, development of Barrett’s esophagus, and progression to esophageal adenocarcinoma. World J Gastroenterol. 2010;16:531–537

    CAS  PubMed  PubMed Central  Google Scholar 

  23. Kan T, Meltzer SJ. MicroRNAs in Barrett’s esophagus and esophageal adenocarcinoma. Curr Opin Pharmacol. 2009;9:727–732

    CAS  PubMed  PubMed Central  Google Scholar 

  24. 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

    CAS  PubMed  Google Scholar 

  25. 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

    CAS  PubMed  PubMed Central  Google Scholar 

  26. Wu X, Ajani JA, Gu J et al. MicroRNA expression signatures during malignant progression from Barrett’s esophagus to esophageal adenocarcinoma. Cancer Prev Res Philadelphia, Pa. 2013;6:196–205

    CAS  Google Scholar 

  27. 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

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Levine DS, Blount PL, Rudolph RE, Reid BJ. Safety of a systematic endoscopic biopsy protocol in patients with Barrett’s esophagus. Am J Gastroenterol. 2000;95:1152–1157

    CAS  PubMed  Google Scholar 

  29. Herrera-Merchan A, Cerrato C, Luengo G et al. miR-33-mediated downregulation of p53 controls hematopoietic stem cell self-renewal. Cell cycle (Georgetown, Tex). 2010;9:3277–3285

    CAS  Google Scholar 

  30. Zhang X, Liu J, Zang D et al. Upregulation of miR-572 transcriptionally suppresses SOCS1 and p21 and contributes to human ovarian cancer progression. Oncotarget. 2015;6:15180–15193

    PubMed  PubMed Central  Google Scholar 

  31. Zhang Y, Ma Y, Xu W et al. Association of microRNA-933 variant with the susceptibility to gastric cancer. J BUON. 2017;22:390–395

    CAS  PubMed  Google Scholar 

  32. Lu JH, Zuo ZX, Wang W et al. A two-microRNA-based signature predicts first-line chemotherapy outcomes in advanced colorectal cancer patients. Cell Death Discov. 2018;4:116

    CAS  PubMed  PubMed Central  Google Scholar 

  33. Jin S, Collin J, Zhu L et al. A novel role for miR-1305 in regulation of pluripotency-differentiation balance, cell cycle, and apoptosis in human pluripotent stem cells. Stem Cells (Dayton, Ohio). 2016;34:2306–2317

    CAS  PubMed Central  Google Scholar 

  34. Lian HW, Zhou Y, Jian ZH, Liu RZ. MiR-323-5p acts as a tumor suppressor by targeting the insulin-like growth factor 1 receptor in human glioma cells. Asian Pac J Cancer Prev APJCP. 2014;15:10181–10185

    PubMed  Google Scholar 

  35. Qiu S, Lin S, Hu D, Feng Y, Tan Y, Peng Y. Interactions of miR-323/miR-326/miR-329 and miR-130a/miR-155/miR-210 as prognostic indicators for clinical outcome of glioblastoma patients. J Transl Med. 2013;11:10

    CAS  PubMed  PubMed Central  Google Scholar 

  36. Momen-Heravi F, Trachtenberg AJ, Kuo WP, Cheng YS. Genomewide study of salivary MicroRNAs for detection of oral cancer. J Dental Res. 2014;93:86s–93s

    CAS  Google Scholar 

  37. Song L, Dai T, Xie Y et al. Up-regulation of miR-1245 by c-myc targets BRCA2 and impairs DNA repair. J Mol Cell Biol. 2012;4:108–117

    CAS  PubMed  Google Scholar 

  38. Zhang XY, Mu JH, Liu LY, Zhang HZ. Upregulation of miR-802 suppresses gastric cancer oncogenicity via targeting RAB23 expression. Eur Rev Med Pharmacol Sci. 2017;21:4071–4078

    PubMed  Google Scholar 

  39. Wang D, Lu G, Shao Y, Xu D. microRNA-802 inhibits epithelial-mesenchymal transition through targeting flotillin-2 in human prostate cancer Biosci Rep. 2017;37.

  40. Wang LQ, Chen G, Liu XY, Liu FY, Jiang SY, Wang Z. microRNA802 promotes lung carcinoma proliferation by targeting the tumor suppressor menin. Mol Med Rep. 2014;10:1537–1542

    CAS  PubMed  Google Scholar 

  41. Cao ZQ, Shen Z, Huang WY. MicroRNA-802 promotes osteosarcoma cell proliferation by targeting p27. Asian Pac J Cancer Prev APJCP. 2013;14:7081–7084

    PubMed  Google Scholar 

  42. Liu W, Wan X, Mu Z et al. MiR-1256 suppresses proliferation and migration of non-small cell lung cancer via regulating TCTN1. Oncol Lett. 2018;16:1708–1714

    PubMed  PubMed Central  Google Scholar 

  43. Li Y, Kong D, Ahmad A, Bao B, Dyson G, Sarkar FH. Epigenetic deregulation of miR-29a and miR-1256 by isoflavone contributes to the inhibition of prostate cancer cell growth and invasion. Epigenetics. 2012;7:940–949

    CAS  PubMed  PubMed Central  Google Scholar 

  44. Liu ZY, Yang L, Chang HY. Clinicopathologic and prognostic relevance of miR-1256 in colorectal cancer: a preliminary clinical study. Eur Rev Med Pharmacol Sci. 2018;22:7704–7709

    PubMed  Google Scholar 

  45. Zhi T, Jiang K, Zhang C et al. MicroRNA-1301 inhibits proliferation of human glioma cells by directly targeting N-Ras. Am J Cancer Res City;2017:982–998.

  46. Yang C, Xu Y, Cheng F et al. miR-1301 inhibits hepatocellular carcinoma cell migration, invasion, and angiogenesis by decreasing Wnt/β-catenin signaling through targeting BCL9. Cell Death Dis. 2017;8:e2999–e2999

    CAS  PubMed  PubMed Central  Google Scholar 

  47. Li CG, Pu MF, Li CZ et al. MicroRNA-1304 suppresses human non-small cell lung cancer cell growth in vitro by targeting heme oxygenase-1. Acta Pharmacol Sin. 2017;38:110–119

    PubMed  Google Scholar 

  48. Felley-Bosco E. Mesothelioma Heterogeneity: Potential Mechanisms. City: MDPI AG; 2019.

  49. Abdelfattah N, Rajamanickam S, Timilsina S, Subbarayalu P, Onyeagucha B, Rao M. Abstract A45: tumor suppressor miR-584-5p regulates MYC and sensitizes MYC-amplified medulloblastoma to vincristine and ionizing radiation. Cancer Res. 2018;78:A45–A45

    Google Scholar 

  50. Ueno K, Hirata H, Shahryari V et al. Tumour suppressor microRNA-584 directly targets oncogene Rock-1 and decreases invasion ability in human clear cell renal cell carcinoma. Br J Cancer. 2011;104:308–315

    CAS  PubMed  Google Scholar 

  51. Wang XP, Deng XL, Li LY. MicroRNA-584 functions as a tumor suppressor and targets PTTG1IP in glioma. Int J Clin Exp Pathol. 2014;7:8573–8582

    PubMed  PubMed Central  Google Scholar 

  52. Xiang X, Mei H, Qu H et al. miRNA-584–5p exerts tumor suppressive functions in human neuroblastoma through repressing transcription of matrix metalloproteinase. Biochim et Biophys Acta BBA Mol Basis Dis 2015;1852:1743–1754

    CAS  Google Scholar 

  53. Wang X, Jin Y, Zhang H, Huang X, Zhang Y, Zhu J. MicroRNA-599 inhibits metastasis and epithelial-mesenchymal transition via targeting EIF5A2 in gastric cancer. Biomed Pharm Biomed Pharm. 2018;97:473–480

    CAS  Google Scholar 

  54. Tian J, Hu X, Gao W et al. Identification a novel tumor-suppressive hsa-miR-599 regulates cells proliferation, migration and invasion by targeting oncogenic MYC in hepatocellular carcinoma. Am J Transl Res. 2016;8:2575–2584

    CAS  PubMed  PubMed Central  Google Scholar 

  55. Bi JW, Zou YL, Qian JT, Chen WB. MiR-599 serves a suppressive role in anaplastic thyroid cancer by activating the T-cell intracellular antigen. Exp Ther Med. 2019;18:2413–2420

    CAS  PubMed  PubMed Central  Google Scholar 

  56. Zhou H, Rigoutsos I. MiR-103a-3p targets the 5’ UTR of GPRC5A in pancreatic cells. RNA New York, NY. 2014;20:1431–1439

    Google Scholar 

  57. Zhi Q, Guo X, Guo L et al. Oncogenic miR-544 is an important molecular target in gastric cancer. Anti-Cancer Agents Med Chem. 2012;13.

  58. Jin S, Dai Y, Li C, Fang X, Han H, Wang D. MicroRNA-544 inhibits glioma proliferation, invasion and migration but induces cell apoptosis by targeting PARK7. Am J Transl Res. 2016;8:1826–1837

    CAS  PubMed  PubMed Central  Google Scholar 

  59. Chen M, Liu YY, Zheng MQ et al. microRNA-544 promoted human osteosarcoma cell proliferation by downregulating AXIN2 expression. Oncol Lett. 2018;15:7076–7082

    PubMed  PubMed Central  Google Scholar 

  60. Sun B, Hua J, Cui H, Liu H, Zhang K, Zhou H. MicroRNA-1197 downregulation inhibits proliferation and migration in human non-small cell lung cancer cells by upregulating HOXC11. Biomed Pharmacother. 2019;117:109041

    CAS  PubMed  Google Scholar 

  61. Zhang J, Zhu Z, Sheng J et al. miR-509-3-5P inhibits the invasion and lymphatic metastasis by targeting PODXL and serves as a novel prognostic indicator for gastric cancer. Oncotarget. 2017;8:34867–34883

    PubMed  PubMed Central  Google Scholar 

  62. Song YH, Wang J, Nie G et al. MicroRNA-509–5p functions as an anti-oncogene in breast cancer via targeting SOD2. Eur Rev Med Pharmacol Sci. 2017;21:3617–3625

    PubMed  Google Scholar 

  63. Provenzale D, Schmitt C, Wong JB. Barrett’s esophagus: a new look at surveillance based on emerging estimates of cancer risk. Am J Gastroenterol. 1999;94:2043–2053

    CAS  PubMed  Google Scholar 

  64. Somerville M, Garside R, Pitt M, Stein K. Surveillance of Barrett’s oesophagus: is it worthwhile? Eur J Cancer Oxford, Engl 1999. 2008;44:588–599

    CAS  Google Scholar 

  65. Sonnenberg A, Soni A, Sampliner RE. Medical decision analysis of endoscopic surveillance of Barrett’s oesophagus to prevent oesophageal adenocarcinoma. Aliment Pharmacol Therapeut. 2002;16:41–50

    CAS  Google Scholar 

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Acknowledgments

This work has been supported in part by the Total Cancer Care Consortium, the Tissue Core Facility, the Molecular Genomics Core, and the Department of Biostatistics and Bioinformatics at the H. Lee Moffitt Cancer Center and Research Institute, an NCI designated Comprehensive Cancer Center (P30-CA076292). We thank Daley Drucker and Paul Fletcher (H. Lee Moffitt Cancer Center and Research Institution) for editorial support. They were not compensated beyond their regular salaries. We also thank Anders Berglund, PhD, Dung-Tsa Chen, PhD, and Braydon Schaible, MS for their role in data analysis. They were not compensated beyond their regular salary.

Funding

MMG Jr. Faculty TSP Pilot Project: 09-33401-15-01.

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Authors and Affiliations

  1. Department of Anatomic Pathology, H. Lee Moffitt Cancer Center and Research Institute, 12902 Magnolia Dr., Tampa, FL, 33612, USA

    James Saller, Kun Jiang, Kevin Neill, Anthony Magliocco & Domenico Coppola

  2. Department of Biostatistics and Bioinformatics, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA

    Yin Xiong

  3. Molecular Genomics Core Facility, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA

    Sean J. Yoder

  4. Department of Gastrointestinal Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA

    Jose M. Pimiento & Luis Pena

  5. Division of Florida Digestive Health Specialists, Gastroenterology Associates of Sarasota, Bradenton, FL, USA

    F. Scott Corbett & Domenico Coppola

  6. Department of Tumor Biology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA

    Domenico Coppola

  7. Department of Chemical Biology and Molecular Medicine, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA

    Domenico Coppola

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  1. James Saller
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Contributions

JS: Drafted the manuscript and participated in the evaluation of the data. KJ: Selected and collected patient samples and performed histopathologic reviews of hematoxylin and eosin stain slides. YX: Performed the bioinformatics and statistical analyses. SY: Participated in project planning, data QC, and provided oversight of RNA extractions and NanoString data generation. KN: Selected and collected patient samples. JMP: Selected patient samples and provided clinical data for BEP. LP: Provided the clinical and endoscopic data of the selected BEP cases. Reviewed the final draft of the manuscript. FSC: Provided the clinical and endoscopic data of the selected BEN cases and participated in the evaluation of the data. Reviewed the final draft of the manuscript. AM: Participated in the evaluation of the molecular data and reviewed the final draft of the manuscript. DC: Designed the study, performed histopathologic reviews of hematoxylin and eosin stain slides, evaluated the study results, and finalized the manuscript.

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Correspondence to Domenico Coppola.

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Saller, J., Jiang, K., Xiong, Y. et al. A microRNA Signature Identifies Patients at Risk of Barrett Esophagus Progression to Dysplasia and Cancer. Dig Dis Sci 67, 516–523 (2022). https://doi.org/10.1007/s10620-021-06863-0

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