Abstract 2716: Role for KMT2C mutation in endometrial cancer pathogenesis

Abstract Background: Endometrial cancer (EC) is the 4th most common cancer to be diagnosed in women. Although EC has reasonable survival rates, there is a disparity gap for African American (AA) women, as they are twice as likely to succumb to metastatic EC. They are also more likely to develop the more severe subtype, uterine serous carcinoma (USC), and high-grade EC. HER2-positive USC can be treated with Trastuzumab, but response varies. The KMT2C gene encodes a lysine methyltransferase involved in histone modification and transcriptional coactivation. Through a meta-analysis of multiple datasets, we identified KMT2C as highly mutated in High Grade Serous Endometrial Cancer (HGSEC) tumors from AA patients when compared to Non-Hispanic White patients. KMT2C was the top gene mutated when comparing differential mutation rates from this data. Methods: To explore the relationship between KMT2C and EC, we transfected 12Z endometrial epithelial cells with KMT2C siRNA to induce transient knockdown and performed western blots with the transfected protein lysates. Additionally, we transfected cells with plasmids containing green fluorescent protein (GFP), Cas9, and 3 different guide RNAs targeting KMT2C to generate stable knockouts. Flow cytometry isolated the GFP+ cells. Using those isolated 12Z CRISPRCas9 knockouts, we performed a final western blot. Results: KMT2C knockdown led to decreased HER2 expression. KMT2C knockdown increased Arid1a expression and minimally increased Snail and Slug expression. GFP expression confirmed successful transfection. CRISPR KMT2C guide 1 silenced some isoforms of KMT2C. Conclusion: Patients who have KMT2C mutations would likely be less responsive to Trastuzumab due to reduced expression of HER2. Arid1a is mutated in about 10% of human cancers and Snail and Slug are markers of epithelial to mesenchymal transition (EMT), so their overexpression in the KMT2C knockdown may have serious implications. More testing should be done related to EC patients with KMT2C mutations and alternate treatment plans need to be explored for this vulnerable subpopulation. Citation Format: Juveria Ali, Swornalata Pukhrambam, Sophia Agrusa, Areebah Qazi, Jessica Back, Greg Dyson, Michele L. Cote, Anna Gottschlich, Mike R. Wilson. Role for KMT2C mutation in endometrial cancer pathogenesis [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 2716.