Abstract B039: Genomic and epigenomic complexity underlies barrett’s esophagus progression to adenocarcinoma
Esophageal adenocarcinoma (EAC) is a highly lethal malignancy with rising incidence and poor survival, and is increasingly recognized as a rare but aggressive cancer subtype with limited therapeutic options. Barrett’s esophagus (BE), the only known precursor, progresses through low-grade dysplasia (LGD) and high-grade dysplasia (HGD) to invasive cancer; however, the molecular mechanisms driving this transition remain poorly understood. While genomic alterations have been cataloged, they do not fully explain the dynamic and heterogeneous progression observed in patients. Emerging evidence suggests that epigenetic plasticity is a central driver of this process, particularly in rare cancers where non-genetic mechanisms contribute disproportionately to disease evolution. In this study, we define the role of epigenetic reprogramming in BE-to-EAC progression by integrating spatial transcriptomics, single-cell analyses, and functional modeling. Using high-resolution CosMx spatial molecular imaging, we profiled BE, LGD, HGD, and EAC tissues to map spatially resolved epithelial and microenvironmental cell states. Our data reveal a progressive increase in transcriptional heterogeneity and enhancer-associated gene expression programs across disease stages, accompanied by early DNA methylation changes and widespread chromatin remodeling. Spatial analyses identify distinct epithelial niches characterized by activation of oncogenic signaling pathways, including receptor tyrosine kinase and MYC-driven programs, as well as secretory and inflammatory phenotypes. These epigenetically defined tumor states are tightly coupled to specific stromal and immune microenvironments, suggesting that niche interactions reinforce and stabilize malignant cell states. Integration of single-cell and spatial datasets demonstrates that enhancer activation correlates with transitions from stable epithelial identity to highly plastic, dysplastic, and malignant phenotypes. Functional studies in organoid and in vitro models further support a model in which chronic injury and inflammation drive epigenetic remodeling, leading to enhancer reprogramming and sustained oncogenic transcriptional activation. This epigenetically driven plasticity promotes tumor evolution, cellular heterogeneity, and progression to invasive cancer. Collectively, our findings position epigenetic plasticity as a fundamental mechanism underlying malignant progression in this rare cancer context. By linking enhancer activation to spatially organized tumor states and microenvironmental interactions, this work provides a conceptual and translational framework for identifying actionable epigenetic vulnerabilities. These insights have the potential to inform early detection strategies and enable precision therapeutic interventions to intercept progression in BE and improve outcomes for patients with EAC. Shilpa S. Dhar, Jaffer S. Ajani. Genomic and epigenomic complexity underlies barrett’s esophagus progression to adenocarcinoma [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Breaking Barriers in the Fight against Rare Cancers; 2026 Jul 18-20; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2026;86(14_Suppl):Abstract nr B039.