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Review
. 2014 Feb;14(2):92-107.
doi: 10.1038/nrc3655.

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

Dominik Sturm  1 , Sebastian Bender  1 , David T W Jones  2 , Peter Lichter  3 , Jacques Grill  4 , Oren Becher  5 , Cynthia Hawkins  6 , Jacek Majewski  7 , Chris Jones  8 , Joseph F Costello  9 , Antonio Iavarone  10 , Kenneth Aldape  11 , Cameron W Brennan  12 , Nada Jabado  7 , Stefan M Pfister  13
Affiliations
Review

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

Dominik Sturm et al. Nat Rev Cancer. 2014 Feb.

Abstract

We have extended our understanding of the molecular biology that underlies adult glioblastoma over many years. By 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 provided deeper insights into gliomagenesis across all age groups, which has highlighted 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 that are 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.

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Figures

Figure 1
Figure 1. Age-based genomic and epigenomic features of biological glioblastoma subgroups
Simplified schematic overview of glioblastoma subgroups depicting recurrent associations between genomic and epigenomic features: (from inside to outside) DNA methylation subclass affiliation (TCGA methylation [REFS, ], and dkfz methylation [REF.]), patient age (years), telomere maintenance mechanisms, mutational status (H3.3 and H3.1 K27, H3.3 G34, IDH1, TP53 and NF1), and copy-number aberrations, grouped by biological subgroup and sorted by patient age. Copy-number states, presence of mutations and ALT positivity are represented by different colours as indicated. Height of bars represents an estimated percentage of cases positive for a specific feature. ALT, alternative lengthening of telomeres; CDKN2A and B, cyclin-dependent kinase inhibitor 2A and 2B; EGFR, epidermal growth factor receptor; G-CIMP, glioma-CpG island methylator phenotype; IDH1, isocitrate dehydrogenase 1; NF1, neurofibromin 1; PDGFRA, platelet-derived growth factor receptor type alpha; RTK, receptor tyrosine kinase; TERT, telomerase reverse transcriptase.
Figure 2
Figure 2. Interplay between the glioblastoma genome and epigenome
Frequent genomic alterations in GBM impacting the epigenomic machinery. Receptor tyrosine kinases (RTKs) are commonly activated by somatic mutations or structural variations (see magnification), leading to PKM2 nuclear translocation and expression of MYC and CCND1. Recurrent somatic mutations in IDH1, IDH2, histone proteins, SETD2 and various other chromatin modifying proteins result in the disruption of multiple epigenetic regulatory processes by affecting histone modification, DNA methylation and chromatin remodelling. Numbers in brackets represent estimated frequencies of alterations observed in GBM of adults and childhood HGG, respectively (see Table 2 for exact numbers; *unknown). 2-HG, 2-hydroxyglutarate; α-KG, α-ketoglutarate; ARID1A, AT-rich interactive domain-containing protein 1A; ATRX, alpha thalassemia/mental retardation syndrome X-linked; CDK4, cyclin-dependent kinase 4; CHD, chromodomain helicase DNA binding protein; CREBBP, CREB-binding protein; EGFR, epidermal growth factor receptor; EZH2, enhancer of zeste homolog 2; FGFR, fibroblast growth factor receptor; HDM, histone demethylase; IDH1, isocitrate dehydrogenase 1; KDM, lysine (K)-specific demethylase; KDR, kinase insert domain receptor; MDM2, mouse double minute 2 homolog; MLL, mixed-lineage leukemia; PDGFRA, platelet-derived growth factor receptor type alpha; PKM2, pyruvate kinase muscle isozyme; PRC2, polycomb repression complex 2; RTK, receptor tyrosine kinase; SEPT14, septin 14; SETD1A, SET domain containing 1A; SETD2, SET domain containing 2; SMARCA2, SWI/SNF related, matrix associated, actin dependent regulator of chromatin, subfamily a, member 2; TACC, transforming acidic coiled-coil.
Figure 3
Figure 3. Telomere maintenance mechanisms in glioblastoma
Maintenance of telomere length is accomplished by different mechanisms in GBM. In normal cells (middle panel), chromosome ends are protected from undergoing non-homologous end joining or homologous recombination by forming a T-Loop structure. Alternative lengthening of telomeres (ALT), thought to be mediated by homologous recombination, is more prevalent in the paediatric setting (upper panel). While mutations in ATRX or DAXX (mediating incorporation of histone H3.3 into pericentromeric and subtelomeric regions) are known to promote ALT, the contribution of p53 loss, H3.3 mutations and/or subtelomeric DNA hypomethylation (such as in GBM harbouring H3.3 G34R/V mutation) needs further elucidation. Telomere length in adult GBM (lower panel) in the presence of functional p53 is mainly maintained by upregulated telomerase (hTERT) expression as a consequence of TERT promoter hotspot mutations C228T or C250T, for example. ATRX, alpha thalassemia/mental retardation syndrome X-linked; DAXX, death-domain associated protein; T-Loop, telomere loop; TERC, telomerase RNA component; TERT, telomerase reverse transcriptase.
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