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<b>Objective</b> Prostate secretory protein of 94 amino acids (PSP94) is a target gene of the EZH2 transcriptional repressor and is often downregulated in prostate cancer; however, its prognostic value is disputed.<b>Methods</b> Immunohistochemical analysis of a tissue microarray of 12, 432 prostate cancer specimens was performed to evaluate PSP94 expression. Correlation of PSP94 expression with tumor phenotype, patient prognosis, <i>TMPRSS2:ERG</i> fusion status, EZH2 expression and <i>PTEN</i> deletion was studied.<b>Results</b> PSP94 expression was increased in benign prostatic hyperplasia; however, it was downregulated in 48% and negative in 42% of the 9, 881 interpretable prostate cancer specimens. The loss of PSP94 expression was inversely correlated to EZH2 expression (<i>P</i> &lt; 0.0001) and largely unrelated to the ERG status, but strongly correlated with high Gleason grade, advanced tumor stage, and nodal metastasis (<i>P</i> &lt;0.0001 each). The fraction of PSP94-negative cancer specimens increased from 40% in pT2 to 52% in pT3b-pT4 (<i>P</i> &lt; 0.0001) and from 40% in Gleason 3+3 = 6 to 46% in Gleason 4+3 = 7 and 60% in Gleason ≥4+4 = 8 (<i>P</i> &lt; 0.0001). Loss of PSP94 was linked to early prostate-specific antigen recurrence, but with little absolute effect (<i>P</i> &lt; 0.0001). However, it provided additional prognostic impact in cancer specimens with <i>PTEN</i> deletion. Loss of PSP94 deteriorated prognosis of cancer patients with <i>PTEN</i> deletion by more than 10% (<i>P</i> &lt; 0.0001). The combination of <i>PTEN</i> deletion and PSP94 loss provided independent prognostic information that was observed in several subgroups defined by classical and quantitative Gleason grade.<b>Conclusions</b> The results of our study suggest that combined PSP94/PTEN analysis can be potentially used in the clinical prognosis of prostate cancer.