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

Key Points

  • Glioblastoma is the most frequent and most aggressive malignant primary brain tumour and remains almost universally incurable in both children and adults.

  • Comprehensive molecular profiling studies have greatly broadened our knowledge of the underlying genomic and epigenomic aberrations that are associated with glioblastoma initiation and progression.

  • Genetic lesions result in disrupted epigenetic control mechanisms by altering histone modifications, DNA methylation and gene expression patterns in a large proportion of glioblastomas.

  • Based on recurrent combinations of genomic and/or epigenomic features with distinct patient characteristics, glioblastomas across all ages are being divided into meaningful biological subgroups, which are likely to guide the design of future clinical trials.

  • The complex interplay between the glioblastoma genome and epigenome opens the way for the development of novel innovative therapeutic strategies that are urgently needed to tackle this deadly brain tumour.

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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Figure 1: Age-based genomic and epigenomic features of biological glioblastoma subgroups.
Figure 2: Interplay between the glioblastoma genome and epigenome.
Figure 3: Telomere maintenance mechanisms in glioblastoma.

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Acknowledgements

This work was principally supported by the PedBrain Tumor Project contributing to the International Cancer Genome Consortium, funded by German Cancer Aid (109252) and by the German Federal Ministry of Education and Research (BMBF; grants #01KU1201A, MedSys #0315416C and NGFNplus #01GS0883). This work was further performed within the context of the I-CHANGE consortium supported by Genome Canada, Genome Quebec, the Canadian Institutes for Health Research (CIHR), McGill University, Montreal, Quebec, Canada, and the Montreal Children's Hospital Foundation.

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Glossary

World Health Organization classification of tumours of the central nervous system

(WHO classification of tumours of the CNS). A classification system in which histological grading is applied as a means of predicting the biological behaviour of a tumour. It ranges from benign tumours (grade I) to highly aggressive, rapidly progressing tumours with frequently fatal outcome (grade IV).

Gliomas

Tumours that have histological features that are similar to normal glial cells; that is, astrocytes (astrocytoma), oligodendrocytes (oligodendroglioma), or ependymal cells (ependymoma). However, the term is often used to imply only astrocytic or oligodendroglial tumours.

Diffuse intrinsic pontine gliomas

(DIPGs). Highly infiltrative glial tumours that occur in the pons. They occur almost exclusively in children, with a peak age at diagnosis of between 5 and 9 years.

Temozolomide

An alkylating chemotherapeutic agent that is used for the treatment of glioblastoma. It triggers tumour cell death through extensive DNA damage.

CpG island methylator phenotype

(CIMP). A DNA methylation pattern of widespread CpG island promoter methylation. CIMP is frequently reported to be associated with distinct tumour subgroups, patient prognosis and response to treatment.

Chromothripsis

Clustered chromosomal rearrangements in one or a few chromosomes during cancer development, which are thought to occur through a one-step catastrophic genomic event.

Double-minute chromosomes

Small circular fragments of extrachromosomal DNA that frequently harbour one or more oncogenes.

High-amplitude focal copy-number aberrations

Small fragments (typically 3 megabases or smaller in size) of amplified or homozygously deleted DNA. Such aberrations often result in numerous copies of oncogenes or the deletion of both copies of tumour suppressor genes.

Alternative lengthening of telomeres

(ALT). A mechanism (or mechanisms) by which 5–10% of human cancers maintain or increase the overall length of their telomeres without the need of increased telomerase activity. The exact molecular mechanism (or mechanisms) of ALT remain elusive, but they may rely on recombination-mediated elongation.

Polycomb repressive complex 2

(PRC2). One of two classes of Polycomb-group proteins. PRC2 has methyltransferase activity and primarily trimethylates histone H3 on lysine 27 (that is, H3K27me3), which is a mark of transcriptionally silent chromatin.

Warburg effect

A predominant production of energy by a high rate of glycolysis followed by lactic acid fermentation in the cytosol that is observed in most cancer cells in the presence of oxygen.

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Sturm, D., Bender, S., Jones, D. et al. Paediatric and adult glioblastoma: multiform (epi)genomic culprits emerge. Nat Rev Cancer 14, 92–107 (2014). https://doi.org/10.1038/nrc3655

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