Abstract: This proposal will define a molecular classification schema for organ-confined prostate cancer. The schema will be based on patterns of gene expression and DNA methylation found within prostate tumors and the surrounding stroma. The aim of the project is to create a method for classifying such tumors based on tumor biology rather than simply on histology. The development of a classification schema based on molecular profiles would improve our ability to treat and manage organ-confined prostate cancer. Four complementary approaches to the generation of molecular profiles will be used. Gene expression molecular profiles will be generated using 1) Affymetrix Gene Chip technology and 2) RNA arbitrarily primed (RAP-PCR) based cDNA array analysis. DNA methylation molecular profiles of will be generated using 1) methylation-sensitive array analysis and 2) restriction landmark genomic scanning (RLGS). The utility and complementarity of each approach in relation to the others will be evaluated. Prospective clinical data will be collected to allow for the correlation of each molecular profile with important tumor characteristics. With the completion of this project we expect that we will have: Defined a molecular profile for organ-confined prostate cancer that will supplant the standard pathologic diagnosis and staging of these tumors. Defined additional profiles that correlate with important clinical characteristics in these patients. Such characteristics should include both important pathologic parameters (i.e. Gleason score, PSA levels, stage), and clinical outcome (likelihood of metastatic disease, likelihood of hormonal, radiation or chemotherapy response, time to progression and survival). Discovering molecular profiles within prostate tumors that prognosticate for patient outcome will greatly improve the quality of life for these patients.