Summary ? Project 1 The goals of this project are to advance understanding of the pathogenesis of pediatric high-grade glioma (HGG), define connections between neural development and gliomagenesis, and generate improved model systems with specific relevance to pediatric HGG. Pediatric HGGs comprise 15-20% of all pediatric CNS tumors, and remain largely incurable, with a two year survival rate of less than 30%. A subset of pediatric HGGs arise within the brainstem as diffuse intrinsic pontine glioma (DIPG), a tumor that arises almost exclusively in children with a two year survival of less than 10%. During the last funding period, we developed improved mouse models of HGG, and conducted in-depth genome-wide studies of pediatric HGG including DIPG. Results from our group and others showed distinct differences in the genetic alterations driving childhood and adult HGG. Most strikingly, recurrent somatic mutations in histone H3 are found in 78% of DIPGs and 36% of HGGs, but only rarely in young adults with glioblastoma, and not in older adult glioblastoma patients. Building on this progress, we propose to determine why histone H3 mutations have a unique selective advantage in the context of developing brain, to determine their contribution to tumorigenesis and the epigenomic landscape of pediatric HGG, and to develop improved model systems of pediatric HGG for biological studies and preclinical testing. Our studies are integrated with those in the other projects that explore mechanisms and genetic and epigenetic signatures driving glioma and medulloblastoma formation, and the identification of therapeutic targets for these devastating diseases. The project receives essential support from the Bioinformatics and Neuropathology Cores for the complex integrated analysis of molecular and histopathological features of tumors generated in model systems and comparisons with primary human tumors.