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Unique genetic and epigenetic mechanisms driving paediatric diffuse high-grade glioma
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Unique genetic and epigenetic mechanisms driving paediatric diffuse high-grade glioma
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Journal Article
Unique genetic and epigenetic mechanisms driving paediatric diffuse high-grade glioma
2014
Overview
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.
There has recently been a flurry of publications on the molecular and genetic basis of diffuse high-grade glioma, a devastating paediatric tumour. In this Review, Jones and Baker integrate these findings to provide new insight into this disease. In particular, the unique selective pressures driving the paediatric disease along with their associated mutations, potential molecular mechanisms and how this information could be harnessed therapeutically, are discussed.
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.
Publisher
Nature Publishing Group UK,Nature Publishing Group
