Abstract: Tumors derived from the same cell type and having similar morphology may nevertheless have a distinctly different clinical behavior and response to therapy. Differences in the genetic lesions in these tumors, as reflected by their gene expression profiles, will provide insight into the mechanisms underlying the divergent clinical spectrum that is observed. Comparative genomic hybridization (CGH) and spectral karyotyping (SKY) are highly complementary novel techniques that examine the entire genome for genetic abnormalities and can supplement and extend conventional cytogenetic studies. In addition, the recently - developed high-density cDNA microarray technology is a very promising method for displaying the pattern of gene expression in tumor tissues. These powerful technologies with their associated informatic systems are now available for translational research. In order to evaluate the information generated by these technologies, an adequate number of well-characterized tumors with detailed clinical data must be available. We propose a multi-institutional, comprehensive molecular analysis of a large series of B-cell non-Hodgkin's lymphoma (NHL). The molecular data obtained will be correlated with the clinical and pathologic information in the extensive databases kept at our institutions to identify clinically and biologically distinct subsets of B- NHL. When unique molecular profiles of clinical and biological significance are identified, we will then define which components within each profile are essential determinants of the clinical features and outcome. Specific confirmatory assays for the expression of key genes, and the cytogenetic abnormalities involving these genes, will be performed. Our longer term goal is to use this information to design a simpler and less expensive microarray for diagnostic use. This “diagnostic chip” could provide rapid molecular characterization of every B-NHL at presentation for optimal treatment decisions and prognostication. We also anticipate the identification of new and significant genetic alterations that will contribute to our understanding of the key events in neoplastic transformation and tumor progression. The insights gained from this project may also identify novel targets for preventive and therapeutic interventions.