Genetic and epigenetic changes drive cell growth and inhibit differentiation of IDH1-mutant glioma.
Major finding: Genetic and epigenetic changes drive cell growth and inhibit differentiation of IDH1-mutant glioma.
Mechanism: MYC and RTK–RAS–PI3K activation and silencing of PRC2-bound genes promote glioma progression.
Impact: IDH1-mutant gliomas are sensitive to BET inhibition, suggesting a potential therapeutic strategy.
About 20% of grade IV gliomas, referred to as glioblastoma multiforme (GBM), arise from the progression of lower-grade gliomas, and without treatment most grade II and III gliomas progress to GBM. However, the mechanisms underlying the malignant progression of low-grade gliomas are poorly understood. As the majority of grade II and III gliomas harbor isocitrate dehydrogenase 1 (IDH1) mutations, Bai and colleagues performed an integrated genomic characterization of 41 IDH1-mutant grade II and III gliomas and their matched higher-grade, progressed samples collected up to 10 years later. Comparison of progressed tumors to their lower-grade matched samples revealed nonlinear tumor evolution, where approximately 30% of mutations and copy-number variations detected in the initial tumors, but not the IDH1 mutation, were lost during tumor progression. Moreover, progressed tumors acquired a median of 21 additional nonsynonymous mutations during progression, as well as copy-number variations. Namely, there were frequent activating alterations in the MYC and receptor tyrosine kinase (RTK)–RAS–PI3K pathways, inactivating mutations in NOTCH and FAT receptors, as well as inactivation of genes involved in epigenetic chromatin remodeling and histone modifications during progression. Progressed gliomas also exhibited upregulation of FOXM1 and E2F networks, as well as DNA hypermethylation of a small number of CpG sites despite reduced overall DNA methylation. These hypermethylated CpG sites enriched for polycomb repressive complex 2 (PRC2) target genes in human embryonic stem cells, which were correspondingly downregulated during glioma progression, keeping glioma cells in a permanently self-renewing state. Furthermore, patient derived IDH1-mutant glioma cells were sensitive to treatment with bromodomain and extraterminal (BET) family inhibitors. These findings reveal genetic and epigenetic mechanisms that promote the progression of lower-grade gliomas to GBM, and suggest that BET inhibitors have potential in the treatment of GBM.
- ©2015 American Association for Cancer Research.