Abstract 5147: Prognostic role of MTAP expression is reversed by the ERG status in prostate cancer treated by radical prostatectomy

Abstract Loss of S-methyl-5′-thioadenosine phosphorylase (MTAP) expression offers an important therapeutic option through synthetic lethality with inhibitors targeting related pathways, and has been linked to resistance to immune checkpoint inhibitors in several tumor types. To better understand the prevalence and clinical relevance of MTAP expression in prostate cancer, a tissue microarray with 17, 747 prostate cancer samples and a molecular and clinical database was analyzed for MTAP expression by immunohistochemistry. Normal prostate glands showed a weak to moderate, predominantly cytoplasmic MTAP positivity of epithelial and stromal cells. In 13, 189 interpretable cancers, a complete loss of MTAP staining as compared to adjacent non-neoplastic cells was seen in 33 (0.3%) tumors, while MTAP staining was considered 1+ in 14.8%, 2+ in 42.2%, and 3+ in 42.7% of tumors. Fluorescence in situ hybridization analysis of 9 MTAP negative cancers confirmed homozygous MTAP deletion in all of these tumors. MTAP staining was significantly stronger in cancers harboring the TMPRSS2:ERG fusion than in TMPRSS2:ERG fusion negative tumors (p<0.0001). A comparison with clinico-pathological features revealed inverse correlations depending on the ERG fusion status: In ERG negative carcinomas, high (3+) MTAP expression was linked to advanced pT stage, high classical and quantitative Gleason grade, and early PSA recurrence in uni- and multivariate analysis (p<0.0001 each). In ERG positive cancers, MTAP expression decreased with advanced pT stage (p<0.0001), classical (p=0.0004) and quantitative Gleason grade (p=0.0005), and low (1+) MTAP expression was significantly linked to early PSA recurrence (p=0.0012). Comparison with 11 previously analyzed chromosomal deletions identified ERG-status-dependent positive or negative associations between MTAP expression and deletions of PTEN and 12p13 (p≤0.0274) suggesting possible functional interactions with PTEN and one or several 12p genes. Taken together, the results of our study demonstrate that MTAP deficiency is exceedingly rare in prostate cancer, while high MTAP expression is a strong and independent marker for poor prognosis in ERG negative cancers. Citation Format: Natalia Gorbokon, Seyma Büyücek, Henning Plage, Neele Heckmann, Ronald Simon, Maximilian Lennartz, Martina Kluth, Elena Bady, Lisa Hornsteiner, Claudia Hube-Magg, Sarah Minner, Eike Burandt, Till S Clauditz, Waldemar Wilczak, Guido Sauter, David Dum, Andrea Hinsch, Hans Heinzer, Alexander Haese, Thorsten Schlomm, Andreas Lübke, Markus Graefen, Stefan Steurer, Christian Bernreuther, Luca Roma, Lukas Bubendorf, Sarah Weinberger. Prognostic role of MTAP expression is reversed by the ERG status in prostate cancer treated by radical prostatectomy [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 5147.