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

作者：Shahriar A. Zamani, Lianlian Wu, Emily L. Black, Alexander Bartram, Alvin W. T. Ng, Maria Secrier, Jacqueline D. Perelman, Ahsen Ustaoglu, E. Ococks, Daniel Jacobson, Ginny Devonshire, Nicola Grehan, Barbara Nutzinger, Adam Freeman, Ahmad Miremadi, Maria O’Donovan, Alexander M. Frankell, Sarah Killcoyne, Paul A. Edwards, Nicola Grehan, Barbara Nutzinger, Aisling M. Redmond, Christine Loreno, Sujath Abbas, Elizabeth Smyth, Maria O’Donovan, Ahmad Miremadi, Shalini Malhotra, Monika Tripathi, Calvin Cheah, Hannah Coles, Curtis Millington, Matthew Eldridge, Maria Secrier, Sriganesh Jammula, Jim Davies, Charles Crichton, Nick Carroll, Richard Hardwick, Peter Safranek, Andrew Hindmarsh, Vijayendran Sujendran, Stephen J. Hayes, Yeng Ang, AD Sharrocks, Shaun R. Preston, Izhar Bagwan, Vicki Save, Richard J. E. Skipworth, Ted R. Hupp, J. Robert O’Neill, Olga Tucker, A Beggs, Philippe Tanière, Sonia Puig, Gianmarco Contino, Tim Underwood, Robert C. Walker, Ben Grace, Jesper Lagergren, JA Gossage, Andrew Davies, Fuju Chang, Ula Mahadeva, Vicky Goh, Francesca D. Ciccarelli, Grant Sanders, Richard Berrisford, David Chan, Ed Cheong, Bhaskar Kumar, L. Sreedharan, Simon L. Parsons, Irshad Soomro, Philip Kaye, John Saunders, Laurence Lovat, Rehan Haidry, Michael Scott, Sharmila Sothi, Suzy Lishman, George B. Hanna, Christopher J. Peters, Krishna Moorthy, Anna Grabowska, Richard Turkington, Damian McManus, Helen G. Coleman, Russell D. Petty, Freddie Bartlett, Helen G. Coleman, Rebecca C. Fitzgerald · 发表于：Nature Medicine · 年份：2026 · DOI：10.1038/s41591-026-04331-8 · 被引用次数：4 · 研究领域：Esophageal Cancer Research and Treatment、Eosinophilic Esophagitis、Microbial metabolism and enzyme function

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.