OT-08 * DISTINCT BRAIN LINEAGE AND STROMAL GENE EXPRESSION PATTERNS IN WNT, SHH, GROUP 3 AND GROUP 4 MOLECULAR SUBGROUPS OF PEDIATRIC MEDULLOBLASTOMA

Abstract

Medulloblastomas are the most common malignant brain tumors in children, comprising distinct molecular subgroups that differ in neuroanatomical predilection, clinical characteristics and overall survival. Here we compare genetic brain lineage and stromal immune profiling in N = 558 pediatric medulloblastomas against N = 426 adult glioblastomas. The medulloblastoma cohort included N = 114 SHH (20%), N = 34 WNT (6%), N = 156 Group 3 (28%), and N = 254 Group 4 (46%). Genetic brain lineage analyses revealed WNT and SHH medulloblastoma to be distinctly astrocytic and astroglial; more similar to adult mesenchymal/classical glioblastoma than other pediatric medulloblastoma. In contrast, Group 4 was distinctly neuronal and oligodendrocytic; more similar to adult proneural/neural glioblastoma than other pediatric medulloblastoma. Interestingly, Group 3 demonstrated no brain lineage enrichment-unlike any other pediatric or adult brain tumor subtype-suggesting a non-CNS etiology for this subgroup known for distinctive large-cell anaplastic histology, aggressive behavior, and uniquely high incidence of metastatic disease. Analysis of stromal immune signatures revealed significant macrophage-specific enrichment in WNT and SHH, but not Group 3 and 4 tumors. These myeloid signatures were characteristic of M2-polarized macrophages, unlike adult glioblastomas, which enriched in both M1 and M2 signatures. While myeloid responses in adult glioblastoma were predictive of poor overall survival, the opposite was true in pediatric medulloblastoma-with improved survival in children with robust immune responses. These data demonstrate that medulloblastoma subtypes display distinct brain lineages and share greater similarities to adult glioblastomas than other pediatric medulloblastomas, further supporting distinct cellular origins for each subtype. Furthermore, innate immune responses were distinctive between subtypes and, in contrast to adult tumors, predictive of good outcomes, suggesting prognostic significance of immune responses differs in children versus adults. Taken together, these findings highlight the distinctiveness of medulloblastoma subtypes with important clinical implications for the design of future targeted molecular therapy and immunotherapy trials in pediatric and adult brain tumor patients.