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

TY - JOUR

T1 - Integrated epidemiological and molecular data inform the relationship between precancer and cancer states of esophageal adenocarcinoma

AU - OCCAMS Consortium

AU - Zamani, Shahriar A

AU - Wu, Lianlian

AU - Black, Emily L

AU - Bartram, Alexander

AU - Ng, Alvin W T

AU - Secrier, Maria

AU - Perelman, Jacqueline D

AU - Ustaoglu, Ahsen

AU - Ococks, Emma

AU - Jacobson, Daniel

AU - Devonshire, Ginny

AU - Grehan, Nicola

AU - Nützinger, Barbara

AU - Freeman, Adam

AU - Miremadi, Ahmad

AU - O'Donovan, Maria

AU - Frankell, Alexander M

AU - Killcoyne, Sarah

AU - Coleman, Helen G

AU - Fitzgerald, Rebecca C

AU - Petty, Russell

N1 - © 2026. The Author(s).

PY - 2026/4/16

Y1 - 2026/4/16

N2 - 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.

AB - 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.

U2 - 10.1038/s41591-026-04331-8

DO - 10.1038/s41591-026-04331-8

M3 - Article

C2 - 41991688

SN - 1078-8956

JO - Nature Medicine

JF - Nature Medicine

ER -