Abstract B018: KDM6A and MTAP expression loss enable identification of a large fraction of low grade non-invasive urothelial neoplasia of the urinary bladder

Abstract The identification of low-grade urothelial neoplasia in cytologic samples or in biopsies with dysplastic lesions poses a particular problem for pathologists in routine diagnostics. Improved diagnosis of low-grade urothelial neoplasia could help to reduce the number of cystoscopic follow-up examinations. 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 is localized on chromosome Xp11. 3, and because of 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). Similarly, S-methyl-5′-thioadenosine phosphorylase (MTAP), a critical enzyme for DNA and RNA synthesis, is co-deleted with the CDKN2A tumor suppressor located on chromosome 9p21 in about 25% of bladder cancers, resulting in reduced or lost protein expression. To study the prevalence and diagnostic potential of immunohistochemical loss of KDM6A and MTAP expression, 928 tumors were analyzed by IHC in a tissue microarray format. The cohort included 628 non-invasive papillary tumors (pTa) and 300 tumors from patients who underwent radical cystectomy for muscle-invasive disease (pT2-4). A complete KDM6A expression loss occurred in 35% of 342 pTa G2 low-grade, 23% of 150 pTa G2 high-grade, 17. 8% of 90 pTa G3 tumors, and 20. 1% of 243 interpretable muscle invasive (pT2-4) cancers (p0. 0001). Within pTa tumors, there was a strong correlation between KDM6A loss and low tumor grade (p=0. 0003), whereas no significant difference was found between pT3 G3 and muscle invasive cancers (p=0. 8828). Complete absence of MTAP expression occurred in 11% of 297 pTa G2 low-grade, 29. 6% of 125 pTa G2 high-grade, 18. 4% of 76 pTa G3 tumors, and 26. 3% of 217 muscle invasive (pT2-4) cancers (p0. 0001). A combined analysis of 702 cancers with interpretable data for KDM6A and MTAP showed that 6. 6% of tumors had expression loss of both KDM6A and MTAP, 20% had KDM6A loss only, and 13% had MTAP loss only. The rate of expression loss of KDM6A and/or MTAP was markedly higher in pTa G2 low (41. 2%) and in pTa G2 high (40. 3%) than in pTa G3 tumors (29%). In summary, our data demonstrate that about 40% of low-grade non-invasive urothelial neoplasias – which are usually not detected by urine cytology – had a completed expression loss of either KDM6A or MTAP. In patients with these alterations, follow-up could be potentially facilitated by immunohistochemistry. Citation Format: Florian Viehweger, Neele Heckmann, Natalia Gorbokon, Henning Plage, Sebastian Hofbauer, Sarah Weinberger, Florian Roßner, Simon Schallenberg, Sefer Elezkurtaj, Maximilian Lennartz, Tim Mandelkow, Elena Bady, Margit Fisch, Thorsten Ecke, Stefan Koch, Nico Adamini, Ronald Simon, Guido Sauter, Tobias Klatte, Thorsten Schlomm, David Horst, Henrik Zecha, Martina Kluth, Sarah Minner. KDM6A and MTAP expression loss enable identification of a large fraction of low grade non-invasive urothelial neoplasia of the urinary bladder abstract. In: Proceedings of the AACR Special Conference on Bladder Cancer: Transforming the Field; 2024 May 17-20; Charlotte, NC. Philadelphia (PA): AACR; Clin Cancer Res 2024;30 (10Suppl): Abstract nr B018.