Journal: Nature medicine
This study examined whether esophageal adenocarcinoma (EAC) can arise without passing through Barrett’s esophagus (BE), or whether BE is effectively an obligate precursor even when not histologically apparent.
Using a prospective cohort of 3,100 EAC patients, the investigators classified cases as BE-positive or BE-negative based on any available clinical or pathologic evidence of BE.
They then compared epidemiologic and clinical features across groups and performed detailed genomic and spatial analyses in subsets, including:
- Whole-genome sequencing in 710 patients
- Multiregional whole-exome sequencing in 87 patients (380 samples)
- Spatial transcriptomic and proteomic profiling to supplement genomic analyses
Key findings:
- Similar BE-associated features: Demographic and genomic characteristics traditionally associated with BE were similar in both BE-positive and BE-negative EAC.
- Early BE molecular signatures: Molecular signatures consistent with early BE evolution were detectable in tumors from both groups, even when histologic BE was absent.
- Association with advanced stage: The only factor that strongly correlated with BE-negative status was more advanced tumor stage; some patients labeled BE-negative had prior documented BE, suggesting overgrowth or loss of recognizable BE with progression.
- Shared evolutionary trajectories: Phylogenetic analyses showed shared evolutionary trajectories between BE-positive and BE-negative EAC, supporting a common developmental pathway.
- Intestinal metaplasia markers: Spatial transcriptomic and proteomic data demonstrated intestinal metaplasia–related lineage markers in both groups.
Overall, the data support a model in which EAC arises through a single, BE-associated pathway, with BE sometimes no longer visible by the time of advanced cancer.
This reinforces the biological centrality of BE in EAC pathogenesis and underscores the importance of effective identification, surveillance, and early intervention in BE for EAC prevention.