Abstract 2267: Mapping genetic risk for Barrett's esophagus and esophageal adenocarcinoma to key tissues and transcriptional regulators

Abstract Background: Esophageal adenocarcinoma (EAC), the most common subtype of esophageal cancer in Western countries, typically arises from Barrett’s esophagus (BE), a pre-neoplastic condition marked by replacement of the normal esophageal epithelium with intestinal metaplasia. Genome-wide association studies (GWAS) have revealed a substantial heritable component of BE/EAC susceptibility, but mechanistic understanding remains limited. Identifying tissues, cell types, and transcriptional regulators mediating genetic risk is essential for elucidating etiologic pathways and defining novel molecular targets for translation. Methods: We employed a permutation-based approach to evaluate the enrichment of BE/EAC-associated variants in open chromatin regions (OCRs) across >50 diverse tissues and cell types. For a subset of implicated tissues, we further assessed enrichment in the binding regions of multiple transcription factors (TFs) using ChIP-seq profiles, with complementary analyses based on DNAse-I footprinting data and motif scanning. Multiple testing correction was implemented using the false discovery rate (FDR<0.05). Results: BE/EAC variants were significantly enriched in OCRs of gastrointestinal tissues, particularly fetal stomach (OR = 1.6, P = 6e-04) and fetal large intestine (OR = 1.5, P = 1.5e-03). Enrichments were also observed in muscle (OR = 1.5, P = 9e-04) and fibroblast (OR = 1.4, P = 8.8e-03) cells, suggesting a broader multi-lineage regulatory landscape. Key TFs implicated in subsequent testing included GATA6 (OR = 3.0, P <1e-04) and GATA4 (OR = 2.2, P = 2e-04) in GI tissues; EZH2 in muscle cells (OR = 5.7, P = 2e-04); and EZH2 (OR = 3.5, P <1e-04) and AR (OR = 1.4, P = 1.2e-03) in fibroblast cells. Conclusions: This study indicates that BE/EAC risk variants act through regulatory elements across diverse tissues, with prominent roles suggested in gastrointestinal, muscle, and stromal cells. The significant enrichment signals for transcription factors such as GATA6, GATA4, and EZH2 underscore their regulatory importance in GI-tract development and BE/EAC pathogenesis. These insights enhance our understanding of the cellular/molecular origins and genetic underpinnings of BE/EAC, providing a promising foundation for experimental and translational studies targeting specific transcriptional regulatory networks. Citation Format: Elnaz Naderi, Xu Zhang, Kathryn Graz, Carlos Maj, Johannes Schumacher, Li Yan, Matthew F. Buas. Mapping genetic risk for Barrett's esophagus and esophageal adenocarcinoma to key tissues and transcriptional regulators [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 2267.