EPIG-04THE CHROMATIN LANDSCAPE OF MEDULLOBLASTOMA

Abstract

Medulloblastoma is a highly malignant pediatric brain tumor characterized by four distinct molecular subgroups - WNT, SHH, Group 3 and Group 4 - each exhibiting disparate clinical features and tumor biology. Genomics has revealed considerable heterogeneity both between and within MB subgroups. Somatic alterations affecting chromatin-modifying genes are among the most penetrant driver events in medulloblastoma, occurring across patient subgroups and suggesting deregulation of the epigenome as an essential event during medulloblastoma pathogenesis. To date, however, the medulloblastoma epigenome remains largely unexplored. In this study, we used histone ChIP-sequencing to systematically characterize the medulloblastoma chromatin landscape in a series of 26 primary fresh-frozen cases encompassing all four subgroups. ChIP-seq performed for six histone marks (H3K4me3, H3K9me3, H3K27me3, H3K27ac, H3K4me1 and H3K36me3) enabled systematic discovery and annotation of chromatin states, revealing the differential representation of polycomb repressed, active promoter, and poised enhancer states across medulloblastoma subgroups. Intriguingly, coverage of the poised enhancer state was significantly higher in Group 4 compared to other medulloblastoma subgroups, exemplified by the priming of enhancers associated with genes involved in neuronal differentiation. Furthermore, integration of chromatin states with sample-matched RNA-seq data demonstrated that the expression of chromatin modifiers and cell cycle genes is correlative with the coverage of different chromatin states in the medulloblastoma epigenome. Ongoing efforts focus on the identification of chromatin state transitions between medulloblastoma subgroups and integration of orthogonal ‘omics’ data to further explore the link between chromatin-modifier deregulation and the epigenome. This comprehensive dataset describing the chromatin landscape of medulloblastoma will dramatically enhance our understanding of the epigenome underlying this malignancy and how it relates to both tumor biology and subgroup-specific cellular origins. These ‘omics’-driven insights are desperately needed to facilitate the development of improved treatment options for this molecularly heterogeneous childhood cancer impoverished of highly penetrant driver genetic events.