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Nat Genet. 2016 Jan;48(1):59-66. doi: 10.1038/ng.3457. Epub 2015 Nov 30.

Integrated genomic characterization of IDH1-mutant glioma malignant progression.

Author information

1
Department of Genetics, Yale School of Medicine, New Haven, Connecticut, USA.
2
Program in Brain Tumor Research, Yale School of Medicine, New Haven, Connecticut, USA.
3
Department of Neurosurgery, Yale School of Medicine, New Haven, Connecticut, USA.
4
Department of Pathology, Yale School of Medicine, New Haven, Connecticut, USA.
5
Department of Neurosurgery, University of Bonn Medical School, Bonn, Germany.
6
Department of General Neurosurgery, University Hospital of Cologne, Cologne, Germany.
7
Department of Neurosurgery, Acıbadem University School of Medicine, Istanbul, Turkey.
8
Translational Medicine, Biomarkers, Gilead Sciences, Inc., Foster City, California, USA.
9
Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
10
Department of Pharmacology, Yale School of Medicine, New Haven, Connecticut, USA.
11
Yale Center for Genome Analysis, Yale School of Medicine, Orange, Connecticut, USA.
12
Department of Neurobiology, Yale School of Medicine, New Haven, Connecticut, USA.
13
Yale Program on Neurogenetics, Yale School of Medicine, New Haven, Connecticut, USA.
14
Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
15
Yale Comprehensive Cancer Center, Yale School of Medicine, New Haven, Connecticut, USA.

Abstract

Gliomas represent approximately 30% of all central nervous system tumors and 80% of malignant brain tumors. To understand the molecular mechanisms underlying the malignant progression of low-grade gliomas with mutations in IDH1 (encoding isocitrate dehydrogenase 1), we studied paired tumor samples from 41 patients, comparing higher-grade, progressed samples to their lower-grade counterparts. Integrated genomic analyses, including whole-exome sequencing and copy number, gene expression and DNA methylation profiling, demonstrated nonlinear clonal expansion of the original tumors and identified oncogenic pathways driving progression. These include activation of the MYC and RTK-RAS-PI3K pathways and upregulation of the FOXM1- and E2F2-mediated cell cycle transitions, as well as epigenetic silencing of developmental transcription factor genes bound by Polycomb repressive complex 2 in human embryonic stem cells. Our results not only provide mechanistic insight into the genetic and epigenetic mechanisms driving glioma progression but also identify inhibition of the bromodomain and extraterminal (BET) family as a potential therapeutic approach.

PMID:
26618343
PMCID:
PMC4829945
DOI:
10.1038/ng.3457
[Indexed for MEDLINE]
Free PMC Article
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