Epigenetic dysregulation: a novel pathway of oncogenesis in pediatric brain tumors

Abstract

A remarkably large number of "epigenetic regulators" have been recently identified to be altered in cancers and a rapidly expanding body of literature points to "epigenetic addiction" (an aberrant epigenetic state to which a tumor is addicted) as a new previously unsuspected mechanism of oncogenesis. Although mutations are also found in canonical signaling pathway genes, we and others identified chromatin-associated proteins to be more commonly altered by somatic alterations than any other class of oncoprotein in several subgroups of childhood high-grade brain tumors. Furthermore, as these childhood malignancies carry fewer non-synonymous somatic mutations per case in contrast to most adult cancers, these mutations are likely drivers in these tumors. Herein, we will use as examples of this novel hallmark of oncogenesis high-grade astrocytomas, including glioblastoma, and a subgroup of embryonal tumors, embryonal tumor with multilayered rosettes (ETMR) to describe the novel molecular defects uncovered in these deadly tumors. We will further discuss evidence for their profound effects on the epigenome. The relative genetic simplicity of these tumors promises general insights into how mutations in the chromatin machinery modify downstream epigenetic signatures to drive transformation, and how to target this plastic genetic/epigenetic interface.

Fig. 1

Central nervous system cellular development and tumorigenesis. Graphic depiction showing differentiation of neural stem cells into neuronal and glial differentiation pathways and subsequent tumorigenesis from presumed cells of origin. CNS Central nervous system, PNET primitive neuroectodermal tumor, AT/RT atypical teratoid/rhabdoid tumor, ETMR embryonal tumor with multilayered rosettes, ETANTR embryonal tumor with abundant neuropil and true rosettes

Fig. 2

Molecular alterations identified in gliomas across the lifespan. Representation of molecular alterations observed in World Health Organization (WHO) grade I–IV astrocytomas and oligodendrogliomas across the age spectrum. Alterations highlighted in red text are shown to have an epigenetic/chromatin remodeling role. GBM Glioblastoma, DIPG diffuse intronsic pontine glioma

Fig. 3

Molecular subgroups of pediatric high-grade gliomas show neuroanatomical preferences. Schematic representation of a sagittal view of the human brain depicting neuroanatomical areas with observed alterations discussed herein. Age of patients harboring these alterations is represented at the right

Fig. 4

Mutations in H3 and the epigenetic machinery in pediatric high-grade gliomas. Graphic representation of histones containing H3.1, encoded by HIST1H3B or HIST1H3C, and H3.3, encoded by H3F3A, variants and mutations affecting these variants in midline and cortical pediatric high-grade gliomas. Effects of these mutations on histone post-translational modifications are indicated