Paediatric and adult glioblastoma: multiform (epi)genomic culprits emerge

Abstract

Preface We have extended our understanding of the molecular biology underlying adult glioblastoma over many years. In contrast, high-grade gliomas in children and adolescents have remained a relatively under-investigated disease. The latest large-scale genomic and epigenomic profiling studies have yielded an unprecedented abundance of novel data and revealed deeper insights into gliomagenesis across all age groups, highlighting key distinctions, but also some commonalities. As we are on the verge of dissecting glioblastomas into meaningful biological subgroups, this Review summarizes the hallmark genetic alterations associated with distinct epigenetic features and patient characteristics in both paediatric and adult disease, and examines the complex interplay between the glioblastoma genome and epigenome.

Molecular subtypes and differentiation programmes of glioma stem cells as determinants of extracellular vesicle profiles and endothelial cell‐stimulating activities

“…While GBMs share certain pathognomonic histological hallmarks, such as high vascularity, pseudopalisading necrosis and infiltrative growth patterns, these tumours are otherwise highly heterogeneous at the molecular and cellular levels [2,3]. This diversity is underscored by a broad spectrum of recurrent oncogenic driver mutations, including amplification of the epidermal growth factor receptor (EGFR), EGFR variant III mutation (EGFRvIII), isocitrate dehydrogenase 1 R132C (IDH1 R132C) mutation and multiple other changes [4].…”

Epigenetic modification in chromatin machinery and its deregulation in pediatric brain tumors: Insight into epigenetic therapies

“…25,26 Comprehensive molecular profiling studies have greatly broadened our knowledge of the underlying genomic and epigenomic aberrations that are associated with the initiation and progression of these brain cancers. 27 …”

“…3 In contrast to adult tumors, pediatric high-grade gliomas commonly have somatic oncogenic gene mutations (H3F3A and HIST1H3B), resulting in replacement of lysine 27 by methionine (K27M) in the encoded histone H3 proteins (Table 1). 27,30 Because it is subject to posttranslational histone modifications, K27 is a key residue in histone H3 variants and can be methylated or acetylated. Substitution of K27 with methionine is thought to contribute to tumorigenesis via defects in chromatin remodeling.…”

“…Substitution of K27 with methionine is thought to contribute to tumorigenesis via defects in chromatin remodeling. 27,30 In a recent study aiming to further understand the impact of K27M-histone H3.3 (H3.3K27M) on tumorigenesis in DIPG, immortalized human astrocytes have been used and were transfected with N-terminally flag-tagged expression vectors containing H3.3WT, H3.3K27M, or empty vector control. 31 In this study, alterations in both expression and methylation profiles of the H3.3K27M expressing cells vs. both wild type (WT) and controls were observed.…”

Comprehensive Genomic Profiling of Recurrent Classic Glioblastoma in a Patient Surviving Eleven Years Following Antineoplaston Therapy

“…Comprehensive genomic profiling was not practiced when the phase II studies of ANP therapy were conducted. However, there have since been exciting advances in molecular research and classification of GBM (Phillips et al, 2006;Verhaak et al, 2010;Van Meir et al, 2010;Sturm, et al, 2012;Bhat et al, 2013;Sturm et al, 2014). Four different molecular subtypes of GBM have been identified: classical, neural, proneural, and mesenchymal (Verhaak et al, 2010;Brennan et al, 2013).…”