The vast majority of men diagnosed with prostate cancer do not die of their disease and can choose to delay or avoid surgical or radiation treatment by undergoing active surveillance. Patients diagnosed with prostate cancer that is categorized as low risk are ideal candidates for active surveillance. Unfortunately, clinical and pathologic parameters available at the time of diagnosis will understage or undergrade prostate cancer in approximately 1/3 of all cases. Therefore, better strategies are needed to risk-stratefy newly diagnosed, low risk prostate cancer. The goal of the proposed project is to evaluate existing RNA-based multi-analyte signatures for risk-stratification at the time of prostate cancer diagnosis. To address the glaring absence of well-established criteria for active surveillance in non-Caucasian men, the validation is performed in parallel in separate Caucasian and African-American cohorts. The project consists of an academic-commercial partnership between Cedars-Sinai Medical Center, Johns Hopkins, University of Toronto, Roswell Park Cancer Institute, and GenomDx Biosciences. The consortium will evaluate signatures trained and tested in large numbers of prostatectomies and confirmed to be predictive of adverse prostate cancer pathology and disease progression. It is now clear that majority of patients who have undergone prostatectomy in the past are candidates for active surveillance; therefore, signatures from prostatectomies are likely to be relevant to diagnostic biopsies from modern active surveillance candidates. The specific aims are (1) to validate biomarkers in prostate needle biopsies predictive of adverse pathology and progression in men considering active surveillance and (2) to test the effects of African-American ethnicity on the biomarker signatures. The consortium is well-positioned to rapidly translate and promote validated signatures since all assays will be performed in a CLIA-approved laboratories, and study investigators have leadership positions in cooperative groups, national professional societies, and national guidelines committees.