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

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

Loss of S-methyl-5′-thioadenosine phosphorylase (MTAP) expression offers a therapeutic option through synthetic lethality and confers resistance to immune checkpoint inhibitors in various cancers. To assess MTAP prevalence in prostate cancer, a tissue microarray of 17,747 samples was analyzed via im...

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Main Authors: Natalia Gorbokon, Seyma Büyücek, Henning Plage, Neele Heckmann, Ronald Simon, Maximilian Lennartz, Martina Kluth, Katharina Teljuk, 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 M Luebke, Markus Graefen, Stefan Steurer, Christian Bernreuther, Luca Roma, Lukas Bubendorf, Sarah Weinberger
Format: Article
Language:English
Published: Elsevier 2025-09-01
Series:Neoplasia: An International Journal for Oncology Research
Subjects:
MTAP
Prostate cancer
Tissue microarray
Prognosis
TMPRSS2:ERG fusion
Immunohistochemistry
Online Access:http://www.sciencedirect.com/science/article/pii/S1476558625000776
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Summary:Loss of S-methyl-5′-thioadenosine phosphorylase (MTAP) expression offers a therapeutic option through synthetic lethality and confers resistance to immune checkpoint inhibitors in various cancers. To assess MTAP prevalence in prostate cancer, a tissue microarray of 17,747 samples was analyzed via immunohistochemistry. Normal prostate glands showed weak to moderate cytoplasmic MTAP staining. In 13,189 interpretable cancers, a complete loss of MTAP staining 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 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 cancers, high (3+) MTAP expression correlated with advanced pT stage, high Gleason grade, and early PSA recurrence (p < 0.0001 each). Conversely, in ERG-positive tumors, MTAP expression decreased with advanced pT stage (p < 0.0001), high 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 functional interactions. 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.
ISSN:1476-5586

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