Abstract 6449: KDM6A expression loss is a common feature in low grade non-invasive urothelial carcinomas of the urinary bladder

Abstract KDM6A, also known as UTX (ubiquitously transcribed X chromosome tetratricopeptide repeat protein) is an epigenetic regulator which is frequently mutated in urothelial carcinoma. Because KDM6A loss causes a dependency on EZH2, a potential therapeutic target, KDM6A analysis may have therapeutic importance. Most data on KDM6A mutations are derived from next generation sequencing (NGS). However, because of the combination of a high rate of truncating KDM6A mutations, the localization of KDM6A on chromosome Xp11.3, and the male predominance in bladder cancer, many KDM6A mutations should result in a complete loss of KDM6A protein expression and become detectable by immunohistochemistry (IHC). To study the prevalence and the potential diagnostic and clinical role of KDM6A expression loss, more than 2,100 tumors were analyzed by IHC in a tissue microarray format. The cohort included 1,128 patients who underwent radical cystectomy for muscle-invasive disease (pT2-4). A complete KDM6A expression loss occurred in 36% of 350 pTa G2 low-grade, 23% of 152 pTa G2 high-grade, and 18.5% of 92 pTa G3 tumors (p=0.0002). As compared to pTa G3 tumors, the frequency of KDM6A expression loss did not differ significantly in pT2 (17.2%), pT3 (21.9%), and pT4 (18.2%) cancers. Within pT2-4 carcinomas, KDM6A staining was unrelated to pT, pN, grade, L-status, V-status, overall survival, recurrence-free survival, and cancer-specific survival (p≥0.18 each). A KDM6A loss was more common in male (22.2%) than in female patients (15.4%; p<0,0001), and within male patients, a KDM6A loss was more frequent in tumors with Y-chromosome loss (36.1%) than in cancers without a Y-chromosome loss (16.3%; p<0.0001). KDM6A expression loss was significantly associated with increased p63 expression (p<0.0001) and high uroplakin 1b staining (p=0.0013) but unrelated to CK20, GATA3, UpK1b, and p53 staining. In summary, our data demonstrate that truncating KDM6A mutations occur in a significant subset of urothelial carcinomas which is linked to low-grade non-invasive cancer, male gender and loss of the Y chromosome. The predominance of KDM6A loss in low grade tumors makes KDM6A IHC a promising new tool for identification of low grade dysplasia in biopsies and early bladder cancer detection in cytology. Citation Format: Florian Viehweger, Natalia Gorbokon, Henning Plage, Sebastian Hofbauer, Kira Furlano, Sarah Weinberger, Bernhard Ralla, Antonia Franz, Annika Fendler, Michela de Martino, Florian Roßner, Simon Schallenberg, Sefer Elezkurtaj, Maximilian Lennartz, Tim Mandelkow, Elena Bady, Andreas H. Marx, Henrik Samtleben, Margit Fisch, Michael Rink, Marcin Slojewski, Krystian Kaczmarek, Thorsten Ecke, Stefan Koch, Nico Adamini, Ronald Simon, Guido Sauter, Joachim Weischenfeldt, Tobias Klatte, Thorsten Schlomm, David Horst, Henrik Zecha, Martina Kluth, Sarah Minner. KDM6A expression loss is a common feature in low grade non-invasive urothelial carcinomas of the urinary bladder [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6449.