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<p>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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年4月16日

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  • Shahriar A. Zamani,
  • Lianlian Wu,
  • Emily L. Black,
  • Alexander Bartram,
  • Alvin W. T. Ng,
  • Maria Secrier,
  • Jacqueline D. Perelman,
  • Ahsen Ustaoglu,
  • Emma Ococks,
  • Daniel Jacobson,
  • Ginny Devonshire,
  • Nicola Grehan,
  • Barbara Nützinger,
  • Adam Freeman,
  • Ahmad Miremadi,
  • Maria O’Donovan,
  • Alexander M. Frankell,
  • Sarah Killcoyne,
  • Paul A. W. Edwards,
  • Nicola Grehan,
  • Barbara Nutzinger,
  • Aisling M. Redmond,
  • Christine Loreno,
  • Sujath Abbas,
  • Elizabeth C. 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 H. Hardwick,
  • Peter Safranek,
  • Andrew Hindmarsh,
  • Vijayendran Sujendran,
  • Stephen J. Hayes,
  • Yeng Ang,
  • Andrew Sharrocks,
  • Shaun R. Preston,
  • Izhar Bagwan,
  • Vicki Save,
  • Richard J. E. Skipworth,
  • Ted R. Hupp,
  • J. Robert O’Neill,
  • Olga Tucker,
  • Andrew Beggs,
  • Philippe Taniere,
  • Sonia Puig,
  • Gianmarco Contino,
  • Timothy J. Underwood,
  • Robert C. Walker,
  • Ben L. Grace,
  • Jesper Lagergren,
  • James 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 Coleman,
  • Russell D. Petty,
  • Freddie Bartlett,
  • Helen G. Coleman,
  • Rebecca C. Fitzgerald

摘要

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.