Abstract
Ependymomas in children occur most commonly in the posterior fossa of the brain and cause significant morbidity and mortality. The pathogenesis of these tumors remains obscure as recent whole genome and whole exome sequencing efforts have not yielded recurrent genetic mutations. These tumors exhibit abnormal CpG island methylation, suggesting that epigenetic alterations may be a significant driver. To gain insights into the epigenetics of childhood ependymomas, we performed mass spectroscopy for histone modifications to discover that H3K27 trimethylation was globally reduced in these tumors. Despite global reduction in H3K27me3, ChIP-sequencing for H3K27me3 revealed genomic enrichment at several loci important for neurodevelopment. In a cohort of 195 childhood posterior fossa ependymoma samples, reduction in H3K27me3 was associated with worse prognosis (p<0.0001). Comparison of DNA methylation and genome-wide H3K27me3 enrichment from both H3K27M mutant diffuse intrinsic pontine gliomas and childhood ependymomas patient samples showed many similarities and pointed to factors that regulate radial glial (neuronal stem cells) development. Human radial glial cells during development exhibit low H3K27me3. Ependymomas with reduced H3K27me3 corresponded to younger children (p<0.0001), arose mainly from the roof of the forth ventricle, exhibited increased evidence of radiologic and histopathologic invasion and exhibited clinical features consistent with previously described PFA subgroup of ependymomas. Together these data suggest that the epigenetics of the developing posterior fossa are closely related to the pathogenesis of childhood brain tumors and have clinical implications for biomarker development and to inform epigenetic approaches to treat PF ependymomas.