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Medulloblastoma (MB), one of the most common malignant childhood brain cancer, consists of heterogeneous subgroup of cerebellar tumors. Four molecular subgroups are classified, of which Groups3 and 4 are poorly characterized. Additionally, MB subtype tumorigenesis and cellular composition remain elusive. Here, we combined multi-omics data, including bulk ChIP-Seq, RNA-Seq data, and scRNA-Seq from medulloblastoma patients with primary tumors, and integrated with whole-genome sequencing data, to address the tumors development and cellular heterogeneity in MB subgroups. First, we identified subgroup-specific enhancers and their targets based on the differential accessibility of H3K27ac signatures and further acquired subgroup-enriched transcription factors. Three distinct transcriptional signatures were extracted from RNA-seq of groups 3 and 4 MB respectively using non-negative matrix factorization and consensus clustering. To illustrate the subtype-specific expressed genes in those subtypes, we applied the Shannon entropy approach to discover genes and lncRNAs that are exclusively active or quiescent in a certain subtype. Single-cell transcriptome analysis demonstrated that SHH subgroup mostly consisted of mature and proliferating GNPs; Group3 tumors contained divergent cells, e.g. GNPs, UBCs, and excitatory CN; while Group4 subgroup derived mainly from UBCs and GluCN. Moreover, deconvolution of bulk RNA-Seq revealed that Group3 subtype1 mostly resembled mitosis and mature GNPs; and subtype2 resembled mitosis GNPs, excitatory CN, and OPCs; while subtype3 resembled UBCs, mitosis and mature GNPs, indicating the cellular origin difference within Group3 tumorigenesis. Genes and lncRNAs specifically expressed in subtype and cell type linked to the subtype MB tumor development and intertumoral cellularity. Taken together, these data enabled us to constructed novel enhancers-target networks that give rise to MB subtyping and cellular heterogeneity and permits the discovery of novel driver genes and pathways in medulloblastoma.

EPCO-33. MULTI-OMICS ANALYSIS REVEALS SUBTYPE-SPECIFIC ENHANCER-TARGET NETWORKS AND TUMOR CELL OF ORIGIN IN GROUPS 3 AND 4 MEDULLOBLASTOMA