Abstract Gastric adenocarcinoma remains a major cause of cancer mortality worldwide. KMT2D, a histone H3K4 methyltransferase, is recurrently altered across solid tumors, yet its role in gastric cancer is not fully defined. We show that KMT2D expression is frequently reduced in gastric tumors, and its loss correlates with significantly poorer overall survival, independent of sex or age. KMT2D-negative tumors exhibit markedly higher EGFR expression compared with KMT2D-positive tumors. Functionally, KMT2D knockdown promotes gastric cancer cell proliferation, migration, invasion, and tumor growth, whereas KMT2D reconstitution suppresses tumor progression in a KMT2D-null model. Conditional Kmt2d deletion in mouse stomach induces gastric enlargement and dysplasia, and Kmt2d-deficient gastric organoids develop low-grade dysplasia with increased proliferation. Mechanistically, KMT2D loss downregulates key transcriptional corepressors, including NCOR2 and RCOR3, leading to activation of multiple oncogenic pathways. KMT2D directly binds and catalyzes H3K4 methylation at the RCOR3 enhancer, supporting its regulatory role. Collectively, these findings define a mechanistic basis for KMT2D loss in gastric tumorigenesis and highlight its potential as a diagnostic biomarker. Citation Format: Liyong Zeng, Fang Cao, Calena J. Brown-Abel, Aryana S. Bhati, Bansi R. Vanparia, Melissa P. Pizzi, Yibo Fan, Gengyi Zou, Tanaya S. Washington, Johnson Amoah, Shay Patel, Arman Dhar, Elisha Deewan, Feng Yin, Yuan-Hung Lo, Min Gyu Lee, Jaffer A. Ajani, Shilpa S. Dhar. KMT2D loss drives gastric cancer tumorigenesis through an RCOR3-dependent mechanism 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 1941.
Zeng et al. (Fri,) studied this question.