The goal of this new proposal is to develop a miR panel as a serum marker to identify biopsy-positive prostate cancer (PCa) patients with a low-risk of harboring aggressive disease. There are several useful pre-treatment risk calculators that use clinical parameters (age, biopsy grade, PSA). These calculators accurately identify high-risk patients defined by clinical parameters. However, there is uncertainty with low/intermediate risk patients with only Gleason grade 3 on biopsy and which of these men require curative treatment. To address this unmet need, we previously identified a serum microRNA (miR) signature that categorized, with extremely high accuracy, a subset of PCa patients with low-risk of harboring aggressive disease. miRs are stable biomarkers resistant to degradation. Our first study used a cohort designed to discover miRs that were differentially present in the pre-surgical sera from a unnatural cohort of 100 PCa patients with either low-grade (Gleason grade 3) or >50 high-grade (Gleason grade 4 5) disease. Using 14 miRs we created a combined miR Score which had clear threshold and a negative predictive value of 0.9 to predict the absence of high-grade PCa among the patients. A unique feature of our discovery study that provides confidence in the predictive ability of the miRs is that the entire radical prostatectomy specimen was step-wised sectioned to ensure absence of high-grade tumors in our low-risk group. As well, none of the PCa patients in our high-grade group, which had abundant Gleason 4 5 tumors, had high levels of the miRs in their serum. Thus were able to perfectly categorize any patient with high serum miR levels as low-grade and low-risk. The experiments in this study were designed to investigate the serum miRs not only as a biomarker, but also potentially as having biological function in PCa. This is distinct from our discovery study because all of the patients for this proposal will be of low to intermediate-risk.