Abstract
Brain tumors are the leading cause of cancer-related death in children. High-grade astrocytomas (HGAs), in particular, are lethal in children across all ages. Integrative genome-wide analyses of the tumor's genome, transcriptome and epigenome, using next-generation sequencing technologies and genome-wide DNA methylation arrays, have provided valuable breakthroughs in our understanding of the pathogenesis of HGAs across all ages. Recent profiling studies have provided insight into the epigenetic nature of gliomas in young adults and HGAs in children, particularly with the identification of recurrent gain-of-function driver mutations in the isocitrate dehydrogenase 1 and 2 genes (IDH1/2) and the epigenetic influence of their oncometabolite 2-hydroxyglutarate, as well as mutations in the histone 3 variant 3 gene (H3F3A) and loss-of-function mutations in the histone 3 lysine 36 trimethyltransferase gene (SETD2). Mutations in H3F3A result in amino acid substitutions at residues thought to directly (K27M) or indirectly (G34R/V) affect histone post-translational modifications, suggesting they have the capacity to affect the epigenome in a profound manner. Here, we review recent genomic studies, and discuss evidence supporting the molecular characterization of pediatric HGAs to complement traditional approaches, such as histology of resected tumors. We also describe newly identified molecular mechanisms and discuss putative therapeutic approaches for HGAs specific to pediatrics, highlighting the necessity for the evolution of HGA disease management approaches.
Highlights
Brain tumors are the leading cause of cancer-related death in children
SETD2 mutations occurred exclusively in tumors of the cerebral cortex, paralleling the age range of IDH1-mutant gliomas (SETD2-mutant tumors median age 16 years, range 1 to 58 years) [55]. These findings suggest that in the context of tumors arising in the cerebral cortex in children and young adults, mutations affecting H3K36 methylation appear to predominate, with H3F3A G34R/V, IDH1 and SETD2 mutations defining about half of all pediatric high-grade gliomas of the cerebral cortex [55], whereas mutations affecting K27 (K27M H3.3 or H3.1) predominate in midline pediatric HGGs (Table 2)
Conclusions and future directions At present, there are no effective therapies for childhood HGG, including glioblastoma multiforme (GBM) and diffuse intrinsic pontine glioma (DIPG), and these tumors remain lethal across the age spectrum
Summary
Infiltrative,nuclear atypia, high mitotic activity, pseudopalissading necroses, florid microvascular proliferation. HGAs in children represent less than 15% of all primary central nervous system neoplasms and encompass tumors mainly located in supratentorial regions including the cortex and the thalamus, similar to adult high-grade tumors, and in the brainstem, a tumor location that is almost exclusive to children, where they are named diffuse intrinsic pontine gliomas (DIPGs) [8]. Duplication of BRAF at chromosomal region 7q34 was shown to define the majority of PAs [18], and was further charac terized in association with the formation of a variety of in-frame fusions between KIAA1549 and BRAF [14] These fusions invariably lead to the loss of the N-terminal regulatory domain and/or constitutive activation of the RAF kinases, resulting in increased MAPK pathway signaling. KIAA1549-BRAF fusion was shown to characterize the vast majority of PA tumors, notably of the cerebellum and optic pathways [12], other mutations/alterations - or ‘hits’ - leading to activation of the MAPK pathway have been described, such as the BRAF V600E mutation, NF1 mutation or loss (in (a) Grade distribution
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