Abstract 5294: Prevalence of KDM6A deficiency in human cancer: a tissue microarray study on 14,814 cancers from 153 different tumor types

Abstract KDM6A (lysine demethylase 6A) is an epigenetic regulator and part of the COMPASS-like complex. Truncating KDM6A mutations commonly occur in cancer and may result in a dependency on EZH2, a potential therapeutic target. Because only one copy of X chromosome genes is normally active in human cells, truncating KDM6A mutations result in a complete expression loss which can be seen by immunohistochemistry. To assess the prevalence of KDM6A expression loss and its role in cancer, a tissue microarray containing 14, 814 samples from 153 different tumor entities was analyzed. In normal tissues, KDM6A staining was ubiquitously seen in nuclei. At least one case with a complete KDM6A expression loss was observed in 58 of 153 tumor categories. KDM6A deficiency predominated in urothelial carcinomas (17.3-42.0%). Tumor entities with a KDM6A deficiency rate of 4-10% included adenocarcinomas of the gallbladder (9.3%), the stomach (up to 8.3%), the pancreas (7.7%), and the prostate (5.9%), endometrioid and serous endometrial carcinoma (up to 7.8%), squamous cell carcinomas (up to 7.5%), papillary renal cell carcinoma (5.1%), hepatocellular carcinoma (4.4%), and malignant melanoma (4.2%), and serous high-grade carcinoma of the ovary (4.1%). Reduced KDM6A expression was associated with advanced pT stage (p=0.0233), high grade (p=0.0002), distant metastasis (p=0.0152), and absence of ER (p<0.0001) and PR (p=0.0045) expression as well as HER2 amplification (p=0.0005) in breast cancer, nodal metastasis in squamous cell carcinomas (p=0.0498), advanced pT stage (p=0.0002), nodal metastasis (p=0.0112), and microsatellite instability (MSI; p=0.0147) in colorectal adenocarcinoma, and with MSI (p=0.0033) in gastric adenocarcinoma. Among gender agnostic cancers, KDM6A deficiency was markedly more common in tumors from males (4.3%) than from females (1.9%; p<0.0001). KDM6A sequencing of 78 bladder cancers revealed truncating mutations in 48.7% and non-truncating mutations in 5.1% of tumors. Truncating but not non-truncating KDM6A mutations were significantly associated with KDM6A expression loss (p<0.0001). All 15 (100%) male patients and 17 of 23 (73.9%) female patients with a truncating KDM6A mutation had a complete KDM6 expression loss. It is concluded that KDM6A deficiency predominates in urothelial neoplasms although it occurs in many different tumor entities, and that both reduced and absent KDM6A correlates with increased aggressiveness. Whether KDM6A deficient cancers are susceptible to EZH2 inhibitors in vivo remains to be seen. Citation Format: Florian Viehweger, Paul Wirth, Natalia Gorbokon, Maximilian Lennartz, Viktor Reiswich, Till Krech, Claudia Hube-Magg, Elena Bady, Lisa Hornsteiner, Guido Sauter, Ronald Simon, Stefan Steurer, Martina Kluth, Andreas H Marx, Andrea Hinsch, Andreas M Luebke, Anne Menz, Clara von Bargen, Frank Jacobsen, Piero Caneve, Ria Schlichter, Sebastian Dwertmann Rico, Simon Kind, Sören Weidemann, Maria Christina Tsourlakis, Waldemar Wilczak, Till S Clauditz, Christian Bernreuther, Sarah Minner. Prevalence of KDM6A deficiency in human cancer: a tissue microarray study on 14, 814 cancers from 153 different tumor types [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 5294.