The Genetic and Epigenetic Basis of Posterior Fossa Ependymoma

Ependymomas are childhood brain tumors that occur throughout the central nervous system, but are most common in the hindbrain, also known as the posterior fossa (PF). Current standard therapy comprises maximal safe surgery and radiation, but not cytotoxic chemotherapy as it does not further increase survival. Despite histological similarity, ependymomas from throughout the neuroaxis likely comprise multiple independent entities, each with a distinct molecular pathogenesis. Transcriptional profiling of two large independent cohorts of ependymoma reveals the existence of two demographically, transcriptionally, genetically, and clinically distinct groups of posterior fossa ependymomas, termed Group A and B. Group A patients are younger, have laterally located tumors with a balanced genome, and are much more likely to exhibit recurrence, metastasis at recurrence, and death as compared to Group B patients. In spite of balanced genomes observed in Group A PF ependymoma, whole-genome and whole-exome sequencing of 47 PF ependymomas reveals an extremely low mutation rate, and zero significant recurrent somatic single nucleotide variants (SNVs). While devoid of recurrent SNVs and focal copy number aberrations, poor prognosis Group A ependymomas exhibit a CpG island methylator phenotype (CIMP). Transcriptional silencing driven by CpG methylation converges exclusively on targets of the polycomb repressive complex 2 (PRC2) that represses expression of differentiation genes through tri-methylation of H3K27. Group A-CIMP+ PF ependymomas are responsive to clinical drugs that target either DNA or H3K27 methylation both in vitro and in vivo. We conclude that epigenetic modifiers are the first rational therapeutic candidates for this deadly malignancy, which is epigenetically de-regulated but genetically bland.Ph.D