Integrated epidemiological and molecular data inform the relationship between precancer and cancer states of esophageal adenocarcinoma

Cancer generally takes years to evolve, and early diagnosis can prevent life-threatening cancer. Establishing a link between precancerous states and cancer is essential for effective screening and prevention. Esophageal adenocarcinoma (EAC) is an increasingly prevalent, poor-outcome cancer, and its presumed precursor, Barrett's esophagus (BE), characterized by intestinal metaplasia, is evident in only about half of cases. Here to test whether BE is a prerequisite to EAC, we integrated epidemiological and clinical characteristics in a prospective cohort of 3,100 patients with EAC for any evidence of BE (BE-positive and BE-negative) and compared genomic features using a subset of 710 patients with whole-genome sequencing and 87 patients (380 samples) with multiregional whole-exome sequencing. Demographic and genomic features typically associated with BE were observed across BE-positive and BE-negative EAC cases. Notably, molecular features consistent with early BE evolution were detected in both phenotypes. Advanced tumor stage was the only variable that corresponded with increased likelihood of BE-negative EAC, including in some patients with a previous BE diagnosis. Phylogenetic analyses revealed shared evolutionary trajectories, and spatial transcriptomic and proteomic analyses demonstrated intestinal metaplasia-associated lineage markers in both groups. These findings suggest a single pathway to EAC, with implications for early diagnosis and prevention strategies.

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Publication Details

Journal
Nature Medicine
Published
2026-04-16
DOI
https://doi.org/10.1038/s41591-026-04331-8
Citations
1
Primary Topic
Esophageal Cancer Research and Treatment
Type
article
Field-Weighted Citation Impact
26.15

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article

Integrated epidemiological and molecular data inform the relationship between precancer and cancer states of esophageal adenocarcinoma

Sarah Killcoyne, Vijayendran Sujendran, Emily L. Black, AD Sharrocks et al.
1 citations
Nature Medicine
Esophageal Cancer Research and Treatment
26.15
article

Integrated epidemiological and molecular data inform the relationship between precancer and cancer states of esophageal adenocarcinoma

Sarah Killcoyne, Vijayendran Sujendran, Emily L. Black, AD Sharrocks, Aisling M. Redmond, Izhar Bagwan, Michael Scott, Ahsen Ustaoglu, Jacqueline D. Perelman, Stephen J. Hayes, Charles Crichton, Calvin Cheah, Yeng Ang, Vicki Save, Francesca D. Ciccarelli, Lianlian Wu, Tim Underwood, Alexander M. Frankell, Suzy Lishman, Shalini Malhotra, Laurence B. Lovat, Shaun R. Preston, L. Sreedharan, Rebecca C. Fitzgerald, Sujath Abbas, E. Ococks, JA Gossage, Andrew Hindmarsh, Paul A. Edwards, Philippe Tanière, Christopher John Peters, Gianmarco Contino, Ahmad Miremadi, Sriganesh Jammula, Adam Freeman, Ginny Devonshire, Ted R. Hupp, Alexander Bartram, Barbara Nutzinger, Krishna Moorthy, Ula Mahadeva, Shahriar A. Zamani, Hannah Coles, Christine Loreno, Curtis Millington, Maria Secrier, Fuju Chang, Ben Grace, J. Robert O’Neill, Monika Tripathi, Peter Safranek, Rehan Haidry, Grant Sanders, Simon L. Parsons, Damian McManus, Elizabeth Smyth, Olga Tucker, Freddie Bartlett, Richard Hardwick, Nick Carroll, A Beggs, Russell D. Petty, Alvin W. T. Ng, Nicola Grehan, David Chan, Richard Berrisford, Andrew Davies, Robert C. Walker, Sonia Puig, Richard Turkington, John Saunders, Matthew Eldridge, Bhaskar Kumar, Helen G. Coleman, Maria O’Donovan, Vicky Goh, Daniel Jacobson, George B. Hanna, Anna Grabowska, Jesper Lagergren, Philip Kaye, Irshad Soomro, Ed Cheong, Richard J. E. Skipworth, Jim Davies, Sharmila Sothi
article en
1 citations

Abstract

Cancer generally takes years to evolve, and early diagnosis can prevent life-threatening cancer. Establishing a link between precancerous states and cancer is essential for effective screening and prevention. Esophageal adenocarcinoma (EAC) is an increasingly prevalent, poor-outcome cancer, and its presumed precursor, Barrett's esophagus (BE), characterized by intestinal metaplasia, is evident in only about half of cases. Here to test whether BE is a prerequisite to EAC, we integrated epidemiological and clinical characteristics in a prospective cohort of 3,100 patients with EAC for any evidence of BE (BE-positive and BE-negative) and compared genomic features using a subset of 710 patients with whole-genome sequencing and 87 patients (380 samples) with multiregional whole-exome sequencing. Demographic and genomic features typically associated with BE were observed across BE-positive and BE-negative EAC cases. Notably, molecular features consistent with early BE evolution were detected in both phenotypes. Advanced tumor stage was the only variable that corresponded with increased likelihood of BE-negative EAC, including in some patients with a previous BE diagnosis. Phylogenetic analyses revealed shared evolutionary trajectories, and spatial transcriptomic and proteomic analyses demonstrated intestinal metaplasia-associated lineage markers in both groups. These findings suggest a single pathway to EAC, with implications for early diagnosis and prevention strategies.

Nature Medicine
Queen's University Belfast (GB), University Hospitals Birmingham NHS Foundation Trust (GB), Nottingham University Hospitals NHS Trust (GB), University of Nottingham (GB), Nanyang Technological University (SG), King's College London (GB), Guy's and St Thomas' NHS Foundation Trust (GB), University of Cambridge (GB), Norfolk and Norwich University Hospital (GB), Royal Surrey County Hospital (GB), Heart of England NHS Foundation Trust (GB), Peterborough City Hospital (GB), Salford Royal NHS Foundation Trust (GB), Cancer Research UK (GB), Wrightington, Wigan and Leigh NHS Foundation Trust (GB), Cambridge University Hospitals NHS Foundation Trust (GB), Ninewells Hospital (GB), University Hospitals Coventry and Warwickshire NHS Trust (GB), Edinburgh Royal Infirmary (GB), University Hospital Southampton NHS Foundation Trust (GB), Karolinska Institutet (SE), University of Manchester (GB), University of Oxford (GB), Cancer Research UK Cambridge Center (GB), Portsmouth Hospitals NHS Trust (GB), Queen's Medical Centre (GB), National Cancer Institute (US), Wythenshawe Hospital (GB), Plymouth Hospital (GB), Department of Health and Human Services (US), University Hospitals Plymouth NHS Trust (GB), University of Southampton (GB), University College London (GB), Imperial College London (GB), University of Birmingham (GB), Cytel (United States) (US), University of Edinburgh (GB)
Cancer Research UK, Medical Research Council
No poverty
Openalex Percentile: Top 1%
Esophageal Cancer Research and Treatment
26.15
DOIOpen Access PDFOpenAlex
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