Objective:

To investigate whether esophageal adenocarcinoma (EAC) can develop independently of Barrett’s esophagus (BE) and to clarify the biological pathways involved.

Key Findings:

• Approximately half of EAC patients do not have detectable BE at diagnosis.
• Patients with and without detectable BE share similar demographic and risk factor profiles.
• Key driver mutations (CDKN2A, TP53, ARID1A) are present in both BE-positive and BE-negative tumors.
• Genomic features and mutational signatures are comparable across both groups.
• Markers of intestinal metaplasia were found in tumors without histologically identifiable BE.

Interpretation:

EAC may develop through a common pathway involving intestinal metaplasia, suggesting that the absence of detectable BE does not rule out underlying precursor changes.

Limitations:

• The study is limited to a specific population in the UK, which may affect generalizability.
• Further research is needed to explore the clinical implications of these findings.

Conclusion:

Molecular and biomarker-based approaches could enhance early detection and risk stratification for EAC, even when BE is not visible.