Liquid biopsy to identify Barrett's oesophagus, dysplasia and oesophageal adenocarcinoma: the EMERALD multicentre study

Jinsei Miyoshi; Alessandro Mannucci; Marco Scarpa; Feng Gao; Shusuke Toden; Timothy Whitsett; Landon J Inge; Ross M Bremner; Tetsuji Takayama; Yulan Cheng; Teodoro Bottiglieri; Iris D Nagetaal; Martha J Shrubsole; Ali H Zaidi; Xin Wang; Helen G Coleman; Lesley A Anderson; Stephen J Meltzer; Ajay Goel; FINBAR-EMERALD collaborative group

doi:10.1136/gutjnl-2024-333364

Liquid biopsy to identify Barrett's oesophagus, dysplasia and oesophageal adenocarcinoma: the EMERALD multicentre study

Gut. 2024 Nov 19:gutjnl-2024-333364. doi: 10.1136/gutjnl-2024-333364. Online ahead of print.

Authors

Jinsei Miyoshi^#^{1

2

3}, Alessandro Mannucci^#^{4

5}, Marco Scarpa⁶, Feng Gao⁷, Shusuke Toden¹, Timothy Whitsett⁸, Landon J Inge⁹, Ross M Bremner⁹, Tetsuji Takayama², Yulan Cheng¹⁰, Teodoro Bottiglieri¹¹, Iris D Nagetaal¹², Martha J Shrubsole¹³, Ali H Zaidi¹⁴, Xin Wang^{15

16

17}, Helen G Coleman¹⁸, Lesley A Anderson¹⁹, Stephen J Meltzer¹⁰, Ajay Goel^{20

4

21}; FINBAR-EMERALD collaborative group

Collaborators

FINBAR-EMERALD collaborative group:
Matteo Fassan, Elisabetta Trevellin, Melania Scarpa, Liam J Murray, Lesley A Anderson, B T Johnston, Rgp Watson, J McGuigan, H R Ferguson, S J Murphy, J V Reynolds, H Comber

Affiliations

¹ Center 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 Department of Gastroenterology and Oncology, Tokushima University Graduate School of Biomedical Sciences, Tokushima, Japan.
³ Department of Gastroenterology, Kawashima Hospital, Tokushima, Japan.
⁴ Department of Molecular Diagnostics and Experimental Therapeutics, Beckman Research Institute of City of Hope, Monrovia, CA, USA.
⁵ Gastroenterology and Gastrointestinal Endoscopy Unit, Vita-Salute San Raffaele University, IRCCS San Raffaele Hospital, Milan, Italy.
⁶ Department of Surgical, Oncological and Gastroenterological Sciences, University of Padua, Padova, Italy.
⁷ Sun Yat-Sen University, The Sixth Affiliated Hospital, Guangzhou, Guangdong, China.
⁸ Cancer and Cell Biology Division, The Translational Genomics Research Institute (TGen), Phoenix, AZ, USA.
⁹ Norton Thoracic Institute, St Joseph's Hospital and Medical Center, Phoenix, AZ, USA.
¹⁰ Division of Gastroenterology and Hepatology, Department Of Medicine And Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, MD, USA.
¹¹ Baylor Scott & White Research Institute, Institute of Metabolic Diseases, Dallas, TX, USA.
¹² Department of Pathology, Radboud University Medical Centre, Nijmegen, Netherlands.
¹³ Department of Medicine, Division of Epidemiology, Vanderbilt University School of Medicine, Nashville, TN, USA.
¹⁴ Esophageal and Thoracic Research Laboratories, Allegheny Health Network Cancer Institute, Allegheny Health Network, Pittsburgh, PA, USA.
¹⁵ Department of Surgery, The Chinese University of Hong Kong, Hong Kong, People's Republic of China.
¹⁶ Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong, People's Republic of China.
¹⁷ Shenzhen Research Institute, The Chinese University of Hong Kong, Shenzhen, People's Republic of China.
¹⁸ Cancer Epidemiology Research Group, Centre for Public Health, Queen's University Belfast, Belfast, UK.
¹⁹ Centre for Health Data Science, Institute of Applied Health Sciences, University of Aberdeen, Aberdeen, UK.
²⁰ Center 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 ajgoel@coh.org.
²¹ City of Hope Comprehensive Cancer Center, Duarte, CA, USA.

^# Contributed equally.

PMID: 39562048
DOI: 10.1136/gutjnl-2024-333364

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.

Keywords: BARRETT'S OESOPHAGUS; DYSPLASIA; OESOPHAGEAL CANCER; TUMOUR MARKERS.

Associated data

ClinicalTrials.gov/NCT06381583