Prostate cancer is the most common cancer in males in Europe, causing over 87,000 deaths in 2006. Early diagnosis and treatment are key factors in determining survival but screening methods based on the commonly-used PSA blood test have low specificity and result in excessive treatment of localized lesions that might never progress to symptomatic cancer. Biomarkers that help determine which of the early stage tumors will remain confined to the prostate and which will progress to an invasive, aggressive form of the disease are urgently needed. Using genome-wide association analysis, we identified 4 distinct common genetic variants that increase the risk of prostate cancer, some of which may have a stronger association with severe disease. Furthermore, by comparing the genotypes of patients with aggressive disease to genotypes of those with a more indolent form, we have identified a large number of candiate markers of disease severity. Here, we plan to take all these inherited variants and test the hypothesis that they can serve as biomarkers for prostate cancer prognosis and outcome. In addition, we have selected two of these variants for genomic and functional studies. Specifically, we will 1. Collect DNA and clinical data from over 8000 prostate cancer cases in four European populations (Iceland, the Netherlands, Romania, UK) 2. Test the utility of inherited prostate cancer risk variants as biomarkers of disease severity, progression and outcome 3. Start dissecting the biological mechanisms that cause increased prostate cancer risk The expected outcome of the project is a) A new prognostic test that predicts clinical outcomes for localized prostate cancer more accurately than existing methods. b) Documentation of the association of genetic risk variants to clinical parameters and outcomes. c) Increased understanding of carcinogenesis of the prostate which may lead to the identification of additional biomarkers or therapeutic targets.