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GI cancer
Original research
Liquid biopsy to identify Barrett’s oesophagus, dysplasia and oesophageal adenocarcinoma: the EMERALD multicentre study
  1. Jinsei Miyoshi1,2,3,
  2. Alessandro Mannucci4,5,
  3. Marco Scarpa6,
  4. Feng Gao7,
  5. Shusuke Toden1,
  6. Timothy Whitsett8,
  7. Landon J Inge9,
  8. Ross M Bremner9,
  9. Tetsuji Takayama2,
  10. Yulan Cheng10,
  11. Teodoro Bottiglieri11,
  12. Iris D Nagetaal12,
  13. Martha J Shrubsole13,
  14. Ali H Zaidi14,
  15. Xin Wang15,16,17,
  16. Helen G Coleman18,
  17. Lesley A Anderson19,
  18. Stephen J Meltzer10,
  19. Ajay Goel1,4,20
  20. On behalf of the FINBAR-EMERALD collaborative group
    1. 1Center for Gastrointestinal Research; Center from Translational Genomics and Oncology, Baylor Scott & White Research Institute and Charles A. Sammons Cancer Center, Baylor University Medical Center, Dallas, TX, USA
    2. 2Department of Gastroenterology and Oncology, Tokushima University Graduate School of Biomedical Sciences, Tokushima, Japan
    3. 3Department of Gastroenterology, Kawashima Hospital, Tokushima, Japan
    4. 4Department of Molecular Diagnostics and Experimental Therapeutics, Beckman Research Institute of City of Hope, Monrovia, CA, USA
    5. 5Gastroenterology and Gastrointestinal Endoscopy Unit, Vita-Salute San Raffaele University, IRCCS San Raffaele Hospital, Milan, Italy
    6. 6Department of Surgical, Oncological and Gastroenterological Sciences, University of Padua, Padova, Italy
    7. 7Sun Yat-Sen University, The Sixth Affiliated Hospital, Guangzhou, Guangdong, China
    8. 8Cancer and Cell Biology Division, The Translational Genomics Research Institute (TGen), Phoenix, AZ, USA
    9. 9Norton Thoracic Institute, St Joseph's Hospital and Medical Center, Phoenix, AZ, USA
    10. 10Division of Gastroenterology and Hepatology, Department Of Medicine And Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, MD, USA
    11. 11Baylor Scott & White Research Institute, Institute of Metabolic Diseases, Dallas, TX, USA
    12. 12Department of Pathology, Radboud University Medical Centre, Nijmegen, Netherlands
    13. 13Department of Medicine, Division of Epidemiology, Vanderbilt University School of Medicine, Nashville, TN, USA
    14. 14Esophageal and Thoracic Research Laboratories, Allegheny Health Network Cancer Institute, Allegheny Health Network, Pittsburgh, PA, USA
    15. 15Department of Surgery, The Chinese University of Hong Kong, Hong Kong, People's Republic of China
    16. 16Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong, People's Republic of China
    17. 17Shenzhen Research Institute, The Chinese University of Hong Kong, Shenzhen, People's Republic of China
    18. 18Cancer Epidemiology Research Group, Centre for Public Health, Queen's University Belfast, Belfast, UK
    19. 19Centre for Health Data Science, Institute of Applied Health Sciences, University of Aberdeen, Aberdeen, UK
    20. 20City of Hope Comprehensive Cancer Center, Duarte, CA, USA
    21. 1Department of Medicine, University of Padova, Padova, Italy
    22. 2Lab of Advanced Translational Research, Veneto Institute of Oncology, IOV-IRCCS, Padova, Italy
    23. 3Queen’s University Belfast, Belfast, UK
    24. 4Belfast Health & Social Care Trust, Belfast, UK
    25. 5St Vincent’s Hospital, Dublin, Ireland
    26. 6National Cancer Registry of Ireland, Dublin, Ireland
    1. Correspondence to Professor Ajay Goel; ajgoel{at}coh.org

    Abstract

    Background There is no clinically relevant serological marker for the early detection of oesophageal adenocarcinoma (EAC) and its precursor lesion, Barrett’s oesophagus (BE).

    Objective To develop and test a blood-based assay for EAC and BE.

    Design Oesophageal MicroRNAs of BaRRett, Adenocarcinoma and Dysplasia (EMERALD) was a large, international, multicentre biomarker cohort study involving 792 patient samples from 4 countries (NCT06381583) to develop and validate a circulating miRNA signature for the early detection of EAC and high-risk BE. Tissue-based miRNA sequencing and microarray datasets (n=134) were used to identify candidate miRNAs of diagnostic potential, followed by validation using 42 pairs of matched cancer and normal tissues. The usefulness of the candidate miRNAs was initially assessed using 108 sera (44 EAC, 34 EAC precursors and 30 non-disease controls). We finally trained a machine learning model (XGBoost+AdaBoost) on RT-qPCR results from circulating miRNAs from a training cohort (n=160) and independently tested it in an external cohort (n=295).

    Results After a strict process of biomarker discovery and selection, we identified six miRNAs that were overexpressed in all sera of patients compared with non-disease controls from three independent cohorts of different nationalities (miR-106b, miR-146a, miR-15a, miR-18a, miR-21 and miR-93). We established a six-miRNA diagnostic signature using the training cohort (area under the receiver operating characteristic curve (AUROC): 97.6%) and tested it in an independent cohort (AUROC: 91.9%). This assay could also identify patients with BE among patients with gastro-oesophageal reflux disease (AUROC: 94.8%, sensitivity: 92.8%, specificity: 85.1%).

    Conclusion Using a comprehensive approach integrating unbiased genome-wide biomarker discovery and several independent experimental validations, we have developed and validated a novel blood test that might complement screening options for BE/EAC.

    Trial registration number NCT06381583.

    • BARRETT'S OESOPHAGUS
    • OESOPHAGEAL CANCER
    • DYSPLASIA
    • TUMOUR MARKERS

    Data availability statement

    Data sharing not applicable as no datasets generated and/or analysed for this study. Data collected for the study, including deidentified participant data and the code, will be made available to others at publication via a signed data access agreement and at the discretion of the investigators’ approval of the proposed use of such data.

    https://doi.org/10.1136/gutjnl-2024-333364

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      Data availability statement

      Data sharing not applicable as no datasets generated and/or analysed for this study. Data collected for the study, including deidentified participant data and the code, will be made available to others at publication via a signed data access agreement and at the discretion of the investigators’ approval of the proposed use of such data.

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      Footnotes

      • JM and AM are joint first authors.

      • X @AlexMannucci, @gaofeng21cn

      • JM and AM contributed equally.

      • Collaborators The FINBAR-EMERALD collaborators included Matteo Fassan and Elisabetta Trevellin (both from the Department of Medicine, University of Padova, Italy) and Melania Scarpa (Lab of Advanced Translational Research, Veneto Institute of Oncology, IOV-IRCCS, Padova, Italy). The Factors INfluencing the Barrett’s Adenocarcinoma Relationship (FINBAR) study group members included the late Professor Liam J. Murray (Queen’s University Belfast), L. A. A. (Queen’s University Belfast), B. T. Johnston (Belfast Health & Social Care Trust), R. G. P. Watson (Belfast Health & Social Care Trust), J. McGuigan (Belfast Health & Social Care Trust), H. R. Ferguson (Belfast Health & Social Care Trust), S. J. Murphy (St Vincent’s Hospital Dublin), J. V. Reynolds (St James’ Hospital, Dublin) and H. Comber (National Cancer Registry of Ireland).

      • Contributors JM and AM are the 'guarantors' who had full access to the study’s data. They took responsibility for the integrity of the data and the accuracy of the data analysis. Conceptualisation: JM, AM, ST, XW and AG. Data curation: JM, AM, FG, ST and AG. Formal analysis: JM, AM, FG and AG. Funding acquisition: XW and AG. Investigation: JM, AM, FG and AG. Methodology: JM, AM, FG, ST, XW and AG. Project administration: MS, TW, YC, TB, IDN, HGC, XW and AG. Resources: MS, TW, LI, YC, TB, IDN, HGC, XW and AG. Software: JM, AM, ST, FG, XW and AG. Supervision: MS, LI, TT, AHZ, SJM, HGC, XW and AG. Validation: JM, AM, MS, MJS, AHZ, SJM, HGC, LAA and AG. Visualisation: AM and AG. Writing–original draft: AM and AG. Writing–review/edits: JM, AM, FG, ST, SJM, TW, LI, TT, YC, TB, IDN, MJS, AHZ, SJM, HGC, LAA, XW and AG.

      • Funding The present work was supported by the CA72851, CA181572, CA184792, CA187956 and CA202797 grants from the National Cancer Institute, National Institute of Health and a grant from Guangdong Basic and Applied Basic Research Foundation (Project No. 2019B030302012), Shenzhen Medical Research Fund (Project No. C2303002) and grants from the Research Grants Council of the Hong Kong Special Administrative Region, China (Project No. 14111522, C4024-22GF, R4007-23) awarded to XW. This work was also partially sponsored by Shenzhen Bay Scholars Program awarded to XW. The FINBAR study was funded by Cancer Focus Northern Ireland (formerly the Ulster Cancer Foundation), the Northern Ireland R&D office and the Health Research Board, Ireland.

      • Disclaimer The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

      • Competing interests None declared.

      • Patient and public involvement Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research.

      • Provenance and peer review Not commissioned; externally peer reviewed.

      • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.