High Serine-arginine Protein Kinase 1 Expression with PTEN Loss Defines Aggressive Phenotype of Prostate Cancer Associated with Lethal Outcome and Decreased Overall Survival

Background: Serine-arginine protein kinase 1 (SRPK1) has been implicated in prostate cancer (PCa) progression. However, its prognostic value and association with ERG and PTEN expression, two of the most common genetic alterations, have not been explored fully. Objective: We assessed the prognostic value of SRPK1 in association with ERG and PTEN in a cohort of patients managed nonsurgically by androgen deprivation therapy (ADT) for advanced disease. Design, setting, and participants: The study cohort consisted of men diagnosed with PCa by transurethral resection of the prostate (TURP; n = 480). The patients were divided into three main groups: incidental (patients with Gleason score [GS] ≤7 with no prior ADT), advanced (patients with GS ≥8 with no prior ADT), and castrate-resistant PCa (patients with prior ADT). Outcome measurements and statistical analysis: A total of 480 TURP samples were assessed by immunohistochemistry for SRPK1, ERG, and PTEN, and results were correlated with Gleason grade group (GG), overall survival (OS), and PCa-specific mortality (PCSM). Results and limitations: High SRPK1 expression was noted in 105/455 (23%) available patient cores. Expression of SRPK1 was associated with Gleason grade grouping (p \u3c 0.0001) with high expression detected in 22/74 (33%) with GG 5. High SRPK1 was not associated with ERG positivity (p = 0.18) but was significantly associated with PTEN intensity (p = 0.001). High SRPK1 was associated with OS (hazard ratio [HR] 1.99; confidence interval [CI]: 1.57–2.54, p \u3c 0.0001) and PCSM (HR 1.64; CI: 1.19–2.26, p \u3c 0.002). Adjusting for Gleason score, patients with high SRPK1 and negative PTEN had the worst clinical outcome for both OS and PCSM compared with other patients (p \u3c 0.0001, HR: 3.02; CI: 1.87–4.88 and HR: 6.40, CI: 3.19–12.85, respectively). Conclusions: High SRPK1 is associated with worse OS and PCSM. Moreover, patients with high SRPK1 expression and loss of PTEN had the worst clinical outcome for OS and cancer-specific mortality. Combined status of SRPK1 and PTEN may provide added value in stratifying patients into various prognostic groups. Patient summary: The expression of serine-arginine protein kinase 1 (SRPK1) combined with PTEN has a significant prognostic role in prostate cancer patients. Patients with high SRPK1 expression and negative PTEN had the worst clinical outcome for overall survival and cancer-specific mortality

Combined loss of TFF3 and PTEN is associated with lethal outcome and overall survival in men with prostate cancer.

BACKGROUND: Trefoil Factor 3 (TFF3) has been implicated in Prostate Cancer (PCa) progression. However, its prognostic value and association with other biomarkers have not been fully explored. We assessed the combined value of TFF3 and PTEN in two cohorts: one is managed surgically for localized PCa and the second is managed non-surgically by androgen deprivation therapy for advanced disease. DESIGN: 228 radical prostatectomies (RP) and 318 transurethral resection of prostate (TURP) samples were assessed by immunohistochemistry (IHC) for TFF3 and by IHC and fluorescent in situ hybridization (FISH) for PTEN. Results of biomarkers expression were correlated with various pathological and clinical outcome parameters including biochemical recurrence (BCR) in the RP cohort and cancer-specific mortality (PCSM) and overall survival (OS) in the TURP cohort. RESULTS: TFF3 expression was detected in 131/226 (57.9%) RP samples and 148/318 (46.5%) of TURP cases. In general, TFF3 positivity was less frequently observed with advanced Gleason Groups. TFF3 expression was also assessed in relation to PTEN expression. Only 15-16% of TFF3-expressed cases were present in association with complete loss of PTEN expression in the TURP and localized cohorts, respectively. Loss of TFF3 expression was not related to BCR after RP, but was prognostic in the non-surgical cohort and associated with decrease OS and PCSM (HR 2.31, CI: 1.67-3.18, p \u3c 0.0001) and (HR 3.99, CI: 2.43-6.56; p \u3c 0.0001), respectively. Adjusting for Gleason score, combined loss of TFF3/PTEN was most associated with OS (HR 2.33, CI: 1.49-3.62; p \u3c 0.0001) and PCSM (HR = 3.44, CI: 1.75-6.78, p \u3c 0.0001). CONCLUSION: The study documents for the first time significant association for combined status of TFF3 expression and PTEN loss in OS and PCSM in patients not managed by surgical intervention. Prospective assessment of PTEN and TFF3 may provide further insight into molecularly subtyping PCa and aid in stratifying patients at risk for lethal disease

Molecular characterization of prostate cancer in Middle Eastern population highlights differences with Western populations with prognostic implication

BACKGROUND: To investigate the incidence and prognostication of ERG, PTEN and SPINK1 protein expressions in prostate cancer cohort of Middle Eastern descent in comparison to published data from Western population. METHODS: Immunohistochemistry for ERG, PTEN and SPINK1 was performed in a cohort of localized PCA (n = 340). The data were correlated to pathological and clinical outcomes and compared to Western populations. RESULTS: ERG expression and PTEN loss were noted in 123/288 (42.7%) and 91/297 (30.6%) of patients, respectively. SPINK1 expression was assessed in a subset of cases, noted in 6/150 (4%) of patients. Only ERG expression was associated with grade groups, being more common in the lower grade groups (1-3 vs 4-5; p = 0.04). In contrast to the Western population, PTEN loss foci were more likely to be ERG negative, observed in 81% of tumor foci and patients with PTEN neg/ERG pos were more likely to exhibit biochemical recurrence (OR 2.831; 95% CI 1.10-726, p = 0.03). This association remained significant in multivariate analysis (OR 2.68; 95% CI 0.98-7.33, p = 0.05), after adjusting for GG, path stage and surgical margin. CONCLUSION: This study documents significant differences in key molecular events in PCA in Middle Eastern population compared to Western populations that could explain differences in PCA incidence, progression and prognostication. ERG, PTEN and SPINK1 genomic alteration occur less frequently and the enrichment of ERG for PTEN loss is not observed. Additionally, patients with combined PTEN loss/ERG positive are at highest risk for BCR vs North American Caucasian population where PTEN loss alone seems to be associated with the worst clinical outcome. The data presented here further support differences in clonal evolution between Middle Eastern and Western population in relation to PCA and add further insight to understanding PCA molecular pathways