Shared dysregulation of long non-coding RNA and developmental gene networks in histone H3 K27M gliomas and PF-A ependymomas.

Abstract

e21523 Background: Diffuse pediatric gliomas harboring a Histone-H3 K27M mutation are more aggressive than H3-wild type gliomas and demonstrate global hypomethylation at the K27 residue1. As a result, these tumors show global aberrant gene expression, resulting in a stem-like proliferative cell population2. Posterior fossa (PF) ependymomas, on the other hand, harbor few significantly recurrent somatic mutations, but PF-A and PF-B subgroups have been defined on the basis of epigenetic differences3. Compared to PF-B, the PF-A subgroup demonstrates H3K27 hypomethylation, aberrant gene expression and aggressive tumor growth4,5. Methods: We recently identified a set of long non-coding RNA (lncRNA) that are transiently expressed in early brain development6, and hypothesized that H3K27M gliomas and PF-A ependymomas may share methylation-related dysregulation of lncRNA networks responsible for maintaining normal differentiation programs. Results: Here we describe a network of regulatory lncRNA with increased expression in both H3K27M gliomas and PF-A ependymomas, as compared to H3-WT gliomas and PF-B ependymomas. We demonstrate that increased expression of this lncRNA network correlates with the over-expression of signaling pathways involved in maintaining a non-differentiated, proliferative phenotype and driving tumorigenesis. Conclusions: We hypothesize that in both H3K27M gliomas and PF-A ependymomas, aberrant global methylation may be driving lncRNA to activate and maintain stem-like states in early neural development, suggesting similarities in epigenetically driven, developmental origins for both tumor types.