Abstract 4652: Prevalence and prognostic role of KDM6A deficiency and overexpression in surgically treated prostate cancer

Abstract KDM6A, also known as UTX (ubiquitously transcribed X chromosome tetratricopeptide repeat protein) is a critical epigenetic regulator which is often subject to truncating mutations and subsequent expression loss in cancer. To interrogate the clinical significance of aberrant KDM6A expression, a tissue microarray containing prostate cancers from patients treated by prostatectomy was analyzed by immunohistochemistry. KDM6A immunostaining was weak in 33.5%, moderate in 52.9%, and strong in 7.3% of 13, 747 interpretable tumors while 880 (6.4%) tumors completely lacked KDM6A staining (KDM6A deficiency). The KDM6A status depended on the TMPRSS2:ERG fusion status. Strong KDM6A staining occurred in only 4.5% of ERG IHC negative, but in 11.1% of ERG IHC positive cancers while KDM6A deficiency occurred in 10.5% of ERG negative, but in only 1.4% of ERG positive cancers (p<0.0001 each). High KDM6A expression was linked to advanced pT, high Gleason grade, nodal positivity, and early PSA recurrence (p<0.0001 each). The prognostic role of high KDM6A expression was independent of pre- (Gleason score from biopsy, cT, PSA) and postoperatively (Gleason score from prostatectomy, pT, pN, R status) available parameters in all tumors (p<0.0001) and in ERG negative (p<0.0001) and positive subgroups (p=0.0049). In contrast, the outcome of KDM6A deficient cancers varied substantially between ERG negative (good prognosis) and ERG positive (bad prognosis) subgroups. In conclusion, the striking independent association of high KDM6A expression with poor prognosis suggests an important role of KDM6A expression in cancer cells which may have clinical utility in prostate cancer. The reciprocal role of KDM6A expression losses in ERG positive and negative cancers indicates a variable, cancer subtype dependent clinical effect of KDM6A deficiency. The clinical effects of anti-EZH2 drugs remains may depend on the ERG status in prostate cancer. Citation Format: Neele Heckmann, Natalia Gorbokon, Maximilian Lennartz, Martina Kluth, Eike Burandt, Till S Clauditz, Waldemar Wilczak, Stefan Steurer, Christian Bernreuther, Elena Bady, Lisa Hornsteiner, Ronald Simon, Hans Heinzer, Alexander Haese, Sarah Minner, Guido Sauter, Thorsten Schlomm, Markus Graefen, Florian Viehweger. Prevalence and prognostic role of KDM6A deficiency and overexpression in surgically treated prostate cancer [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 4652.