DESCRIPTION (provided by applicant): Recent suggests that in the U.S. prostate cancer is over-detected and over-treated resulting in significant morbidity and financial costs. These problems are the product of poor sensitivity and specificity serum Prostate Specific Antigen (PSA) as a screening tool, leading to many unnecessary biopsies that find small and predominantly indolent prostate tumors. While many prostate cancers should be managed with active surveillance, uncertainties surrounding available clinical tools of aggressiveness (such as PSA, Gleason score and clinical stage) will often drive patients and physicians to treatment. Attempts to improve prognostication using candidate biomarkers, mostly discovered from genomic analyses of large pieces of cancers, have had few successes, and available molecular tools provide only modest prediction at best. Clearly, a better understanding of the early molecular genetic events in prostate cancer is desperately needed. We hypothesize that early prostate cancer arises from definable molecular alterations in precursor lesions and progresses as a result of acquired lesions that confer aggressive features in a subpopulation of cells in precursor lesions and/or early tumors. In addition, we hypothesize that at each step, there are downstream molecular alterations that confer, in a probabilistic sense, the ability for some lesions to grow and spread and in others an indolent phenotype (dead end lesions). As such, defining the earliest genomic events, the evolutionary pathways to invasive carcinoma, the final constellation of genomic alterations, and the extent of genomic heterogeneity (the building blocks for evolution), should illuminate the key genomic features distinguishing good and bad outcome prostate cancer. In depth characterization of early lesions has been constrained by limitations of conventional histology tools (prostate cancer precursors can only be reliably identified in fixed tissues) and of available genomic and proteomic technologies (which do not work well on fixed tissues). To address the challenges we wil take advantage of technologies we have developed to analyze small samples in both fixed and frozen tissue to provide a complete picture of the early events in prostate carcinogenesis. We propose 1) to investigate the early genomic evolution of good and bad outcome prostate cancer in histologically defined prostate cancers and precursor lesions in fixed tissues; and 2) to define the genomic heterogeneity of good and bad outcome prostate cancer and the downstream consequences in transcript, protein and glycoprotein expression in frozen tissues. An integrated approach using fixed and frozen tissues will allow us to delineate the early genomic lesions in prostate cancer, define which are selected to evolve into more aggressive and which end up as non-aggressive (dead end) lesions, and characterize the downstream effects of these selected changes in cellular transcription, protein expression and protein glycosylation. A systematic study of the events in prostate cancer during its development and evolution will help address the issues of over- treatment by providing prognostic features and biomarkers that help select men for definitive treatment or observation.