Abstract Germline mutations in CDH1 are associated with early-onset diffuse gastric adenocarcinoma. There is no gold standard for screening and management, and endoscopic surveillance is often insufficient for detecting early disease. Prophylactic gastrectomy is maximally preventive but is a major operation associated with significant morbidity and extensive lifestyle modifications. Therefore, there is a need to better understand the pathophysiological features underlying carcinogenesis in the setting of CDH1 mutation. To address this gap, we performed spatial transcriptomic profiling on 29 formalin-fixed paraffin-embedded sections from 8 patients with various stages of gastric adenocarcinoma, including one patient with a germline CDH1 mutation (c.1936+5GA) found to have multifocal intramucosal poorly cohesive signet-ring cell carcinoma. Image-based cell segmentation and subcellular transcript detection enabled identification of diverse epithelial cell types, as well as their stromal and immune neighborhoods. Epithelial cells from the specimen harboring the germline CDH1 mutation expressed lower levels of CDH1 compared with other samples. Although morphologically normal-appearing, mucosal layers in these sections exhibited altered transcriptomic profiles characterized by an expanded epithelial population with high MUC1 expression. MUC1 is a transmembrane glycoprotein frequently upregulated in various cancers, with a cytoplasmic domain capable of interacting with several intracellular signaling partners, particularly β-catenin. Gene regulatory network analysis revealed a gradient of CTNNB1/β-catenin activation program, suggesting a potential interplay between CDH1 loss-of-function, MUC1 overexpression, and β-catenin pathway dysregulation. These findings reveal a novel MUC1-overexpressing epithelial population associated with CDH1 mutation and early-onset gastric adenocarcinoma, providing new rationales for developing surveillance biomarkers and targeted therapies. Citation Format: Chuner Guo, Rosyli F. Reveron-Thornton, Xiaomo Li, James P. Agolia, Maria Moozhiyil Korah, Peter Yuxin Xie, Amanda Gonçalves, Angela Tabora, Lily Xia, Natali Barakat, George Poultsides, Byrne Lee, Amanda R. Kirane, Deshka Foster, Michael T. Longaker, Gregory W. Charville, Daniel Delitto. A MUC1-overexpressing epithelial population is associated with CDH1 loss-of-function gastric adenocarcinoma abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 2270.
Guo et al. (2026) studied this question.