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Unique genetic and epigenetic mechanisms driving paediatric diffuse high-grade glioma

Key Points

  • Diffuse high-grade gliomas (HGGs) carry a dismal prognosis in both children and adults; however, genome-wide molecular analyses have shown that the disease pathogenesis differs significantly between these age groups.

  • There are at least several distinct subgroups of paediatric diffuse HGG based on clinical features and recurrent mutations.

  • Diffuse intrinsic pontine gliomas (DIPGs) arise in the brainstem, occur almost exclusively in children and are incurable.

  • Aberrant epigenetic regulation has an important role in paediatric HGGs, with 'hotspot' K27M histone H3 mutations found in nearly 80% of DIPGs, and alternative G34R or G34V mutations found in paediatric HGGs of the cerebral hemispheres.

  • Recurrent mutations of the bone morphogenetic protein (BMP) receptor activin receptor type 1 (ACVR1; also known as ALK2) are restricted to the youngest patients with DIPG, highlighting crucial connections between development and gliomagenesis.

  • HGGs in children who are less than three years of age contain very few genomic abnormalities and recurrent gene fusions, and have a better outcome than HGGs in older children.

  • An improved understanding of the oncogenic mutations driving paediatric diffuse HGG has identified new potential therapeutic targets and shown that different strategies will be needed to combat this disease in children and adults.

Abstract

Diffuse high-grade gliomas (HGGs) of childhood are a devastating spectrum of disease with no effective cures. The two-year survival for paediatric HGG ranges from 30%, for tumours arising in the cerebral cortex, to less than 10% for diffuse intrinsic pontine gliomas (DIPGs), which arise in the brainstem. Recent genome-wide studies provided abundant evidence that unique selective pressures drive HGG in children compared to adults, identifying novel oncogenic mutations connecting tumorigenesis and chromatin regulation, as well as developmental signalling pathways. These new genetic findings give insights into disease pathogenesis and the challenges and opportunities for improving patient survival in these mostly incurable childhood brain tumours.

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Figure 1: Brain regions and selective mutations distinguish subgroups of paediatric high-grade glioma (HGG).
Figure 2: Mutational burden of paediatric high-grade glioma (HGG).
Figure 3: Recurrent mutations activate PI3K and MAPK signalling pathways in paediatric high-grade glioma (HGG).
Figure 4: Histone and chromatin modifier mutations in paediatric high-grade glioma (HGG) and diffuse intrinsic pontine glioma (DIPG).
Figure 5: Activin receptor type 1 (ACVR1) mutations in diffuse intrinsic pontine glioma (DIPG).

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Acknowledgements

The recent progress in defining genetic abnormalities in diffuse intrinsic pontine glioma (DIPG) was only possible owing to the altruistic tissue donation by patients and families through autopsy or biopsy. The authors thank D. Ellison for helpful comments. C.J. acknowledges support from the National Health Service funding to the National Institute of Health Research Biomedical Research Centres and support from the Cancer Research UK Genomics Initiative, and S.J.B. acknowledges support from the US National Institutes of Health (P01CA096832) and the American Lebanese and Syrian Associated Charities (ALSAC).

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Correspondence to Chris Jones or Suzanne J. Baker.

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Glossary

Pons

The portion of the brainstem between the midbrain and the medulla oblongata.

Supratentorial

Pertaining to brain regions above the tentorium cerebelli, which separates the cerebellum from the occipital and temporal lobes of the cerebral cortex.

Stereotactic

A system of three-dimensional coordinates that is used in surgery to locate a precise position.

Chromothripsis

Local chromosome shattering in which complex rearrangements with multiple interconnecting breakpoints correspond to genomic segments of oscillating copy number states.

Exophytic

Growing outward beyond the surface from which it originates.

Pilocytic astrocytomas

Low-grade (grade I) astrocytomas, which are the most common primary brain tumour of childhood.

Ganglionic eminences

Transient structures in the embryonic telencephalon that guide tangential cell migration.

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Jones, C., Baker, S. Unique genetic and epigenetic mechanisms driving paediatric diffuse high-grade glioma. Nat Rev Cancer 14, 651–661 (2014). https://doi.org/10.1038/nrc3811

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