Frequent driver mutations in histone H3.3 and chromatin remodeling genes in paediatric glioblastoma
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ABSTRACT:
ORGANISM(S): Homo sapiens
SUBMITTER: Schwartzentruber J
PROVIDER: S-ECPF-GEOD-34824 | biostudies-other | 2012 Feb
REPOSITORIES: biostudies-other
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Project description:Whole exome sequencing identified frequent driver mutations in a series of paediatric glioblastomas We used microarray-based profiling to investigate differences in gene expression according to mutational status of driver genes RNA from 27 primary tumor samples was subject to QC by Agilent BioAnalyser analysis and then hybridised to an Affymetrix U133 Plus2 gene expression array
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Project description:Whole exome sequencing identified frequent driver mutations in a series of paediatric glioblastomas We used microarray-based profiling to investigate differences in gene expression according to mutational status of driver genes
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Project description:UNLABELLED:Children and young adults with glioblastoma (GBM) have a median survival rate of only 12 to 15 months, and these GBMs are clinically and biologically distinct from histologically similar cancers in older adults. They are defined by highly specific mutations in the gene encoding the histone H3.3 variant H3F3A , occurring either at or close to key residues marked by methylation for regulation of transcription—K27 and G34. Here, we show that the cerebral hemisphere-specific G34 mutation drives a distinct expression signature through differential genomic binding of the K36 trimethylation mark (H3K36me3). The transcriptional program induced recapitulates that of the developing forebrain, and involves numerous markers of stem-cell maintenance, cell-fate decisions, and self-renewal.Critically, H3F3A G34 mutations cause profound upregulation of MYCN , a potent oncogene that is causative of GBMs when expressed in the correct developmental context. This driving aberration is selectively targetable in this patient population through inhibiting kinases responsible for stabilization of the protein. SIGNIFICANCE:We provide the mechanistic explanation for how the fi rst histone gene mutation inhuman disease biology acts to deliver MYCN, a potent tumorigenic initiator, into a stem-cell compartment of the developing forebrain, selectively giving rise to incurable cerebral hemispheric GBM. Using synthetic lethal approaches to these mutant tumor cells provides a rational way to develop novel and highly selective treatment strategies
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