Abstract IA15: The unique genomic and epigenomic landscape of pediatric high-grade glioma

Abstract

Abstract Diffuse high-grade gliomas (HGGs) of childhood are a spectrum of disease with devastatingly poor outcome. Despite similar histological features, pediatric HGGs arise from a broader distribution of anatomical locations when compared to adults, with approximately 50% arising in the brainstem as diffuse intrinsic pontine glioma (DIPG), a disease found almost exclusively in children. Recent genome-wide studies provided abundant evidence that unique selective pressures drive HGG in children compared to adults, identifying novel oncogenic mutations connecting tumorigenesis and chromatin regulation as well as developmental signaling pathways. The striking association between frequencies of specific mutations with spatiotemporal pattern of HGG formation in children further highlights context-dependent connections between developmental states and oncogenic drivers. Activating mutations in the BMP receptor ACVR1 are found exclusively in the youngest subgroup of DIPG patients, and not identified in HGGs outside the brainstem. Recurrent mutations in histone H3 establish a critical role for epigenetic regulation in disease pathogenesis of childhood HGG. H3K27M mutations occur in nearly 80% of DIPGs and more than half of HGGs arising in midline structures outside the brainstem such as the thalamus. In contrast, approximately 15% of HGGs arising in the cerebral cortex have an alternative H3 mutation, G34R/V, and are predominantly found in older adolescents and young adults. To study these mutations in the developing mammalian brain, we generated conditionally activated, epitope tagged H3f3a knock-in mice to express K27M, G34R or non-mutated H3.3 proteins from the endogenous H3f3a locus. We will present early analyses of these new oncohistone mouse models. Citation Format: Jon D. Larson, Andre B. Silveira, Lawryn H. Kasper, Alexander K. Diaz, Xiaoyan Zhu, Suzanne J. Baker. The unique genomic and epigenomic landscape of pediatric high-grade glioma. [abstract]. In: Proceedings of the AACR Special Conference: Developmental Biology and Cancer; Nov 30-Dec 3, 2015; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Res 2016;14(4_Suppl):Abstract nr IA15.