Prognostic role of high 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 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.