Small Extracellular Vesicle-Derived microRNAs Stratify Prostate Cancer Patients According to Gleason Score, Race and Associate with Survival of African American and Caucasian Men

SIMPLE SUMMARY: Novel biomarkers are needed to guide prognosis and treatment of aggressive forms of prostate cancer (PCa). In this study, small extracellular vesicles (sEVs)-derived microRNAs (miRs) are used to predict aggressive phenotypes and ancestral background of PCa patients. Two cohorts was used to study the diagnostic and prognostic utility of sEV-associated miRs in predicting aggressive forms of PCa in African American (AA) and Caucasian (CA) men. In training cohort, miR profiling was performed and top-ranked sEV-associated miRs were then validated in two independent confirmatory cohorts comprising 150 plasma samples. Results revealed that sEV-associated miR-6068 and miR-1915-3p were enriched in PCa patients compared to healthy subjects. sEV-associated miR-6716-5p and miR-3692-3p distinguished AA from CA men and low from high Gleason score. However, miR-1915-3p was the only studied miR associated with longer recurrence-free survival as independent prognostic marker. ABSTRACT: The utility of small extracellular vesicles (sEVs)-derived microRNAs (miRs) to segregate prostate cancer (PCa) patients according to tumor aggressiveness and ancestral background has not been fully investigated. Thus, we aimed to determine the diagnostic and prognostic utility of sEV-associated miRs in identifying aggressive PCa in African American (AA) and Caucasian (CA) men. Using a training cohort, miR profiling was performed on sEVs isolated from plasma of PCa patients. Top-ranked sEV-associated miRs were then validated in 150 plasma samples (75 AA and 75 CA) collected from two independent cohorts; NIH (n = 90) and Washington University (n = 60) cohorts. Receiver operating characteristic (ROC) curve, Kaplan–Meier and Cox proportional hazards regression were used to assess these miRs as clinical biomarkers. Among nine top-ranked sEV-associated miRs, miR-6068 and miR-1915-3p were enriched in sEVs collected from PCa patients compared to healthy volunteers. Moreover, miR-6716-5p and miR-3692-3p segregated AA from CA men and low from high Gleason score (GS), respectively. Upregulation of sEV-associated miR-1915-3p, miR-3692-3p and miR-5001-5p was associated with improved survival time, and only miR-1915-3p was associated with longer recurrence-free survival (RFS) as an independent prognostic marker. Taken together, we identified novel sEV-associated miRs that can differentiate PCa patients from normal, AA from CA and high from low GS and predicts RFS.