Despite its widespread use, serum Prostate-Specific Antigen (PSA) has limited accuracy as a prostate cancer biomarker, and new biomarkers are needed to improve early detection of aggressive prostate cancers. Through a collaborative effort in prostate cancer biomarker development, investigators assembled herein have identified avenues for prostate cancer early detection based on biological consequences of alpha-methylacyl-CoA racemase (AMACR) expression in cancerous, but not normal, prostate tissue. Preliminary data indicate that circulating anti-AMACR autoantibodies are detectable in the peripheral blood of prostate cancer patients at higher rates than among control patients. Moreover, we observed higher anti-AMACR auto-antibody titers in sera of patients that had cancers with aggressive pathological features than among patients with more indolent prostate cancer. To build upon these preliminary data, we have assembled a multi-disciplinary, multi-institutional team of investigators to establish a center for the clinical validation of such AMACR-targeted as well as other candidate novel prostate cancer biomarkers at 4 institutions (Beth Israel-Deaconess Medical Center, Brigham and Women's Hospital, Dana Farber Cancer Institute, and the University of Michigan). The primary hypothesis of this proposal is that a humoral immune response to AMACR (as a prototype of various clinical measures related to prostate cancer-associated AMACR expression) is significantly associated with presence and severity of prostate cancer, and provides an opportunity for improvements in early detection of prostate cancer. This hypothesis will be addressed through evaluation of serum collected from three complementary clinical cohorts. Each of these cohorts provides complementary strengths and limitations in evaluating three aims that together address the study hypothesis as follows: 1. To compare specificity of anti-AMACR antibody presence to the specificity of PSA for detecting prostate cancer in a prospective case-control cohort of men undergoing prostate biopsy. 1800 biopsy cases will be enrolled for this Aim. 2. To validate the accuracy of humoral responses against tissue biomarkers, including AMACR, in detecting cancers and gauging cancer severity in the Physicians' Health Study cohort, a community-based cohort of physicians with and without prostate cancer. 500 prostate cancer cases and 1500 controls will be evaluated for this Aim. 3. To evaluate whether anti-AMACR antibody or presence of other humoral responses against prostatic tissue biomarkers) can distinguish aggressive prostate cancers from early cancers at lower risk for extra-prostatic spread in a cohort of men treated for prostate cancer. 1500 prostate caner cases will be evaluated for this Aim. We will collect peripheral blood and relevant clinical information from an aggregate total of 4700 subjects between the 3 Aims combined, and will extend these specimens for other, collaborative biomarker studies of the EDRN.