ABSTRACT Diffuse large B cell lymphoma (DLBCL) is the most common form of blood cancer and is characterized by a striking degree of genetic heterogeneity. It has been known for some time that African American patients have poorer outcomes than Caucasian patients. After correcting for potential differences in socioeconomics and access to care, our data indicate that the poorer outcomes in African Americans arise primarily from distinct genetics of their tumors. The underlying genetic causes of these poorer outcomes have not been studied systematically. Here, we propose to investigate tumor and germline genetics of African Americans to comprehensively understand the genetic basis of their poorer outcomes. Preliminary genomic analysis of African American DLBCL patients has revealed more frequent mutations in histone methyltransferase genes and other genes. In this proposal, we seek to comprehensively define the genetic origins of poor outcomes in African Americans with DLBCL and perform functional characterization of selected genomic alterations.