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Integrated genomic characterization of IDH1 mutant Glioma malignant progression

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 Isocitrate Dehydrogenase 1 (IDH1) mutant gliomas, 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, copy number, gene expression and DNA methylation profiling, demonstrated non-linear clonal expansion of the original tumors and identified oncogenic pathways driving progression. These include activation of the MYC and RTK-RAS-PI3K pathways, up-regulation of the FOXM1- and E2F2-mediated cell cycle transition genes, as well as epigenetic silencing of developmental transcriptional factors 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 extra-terminal (BET) family as a potential therapeutic approach.

Click on a Dataset ID in the table below to learn more, and to find out who to contact about access to these data

Dataset ID Description Technology Samples
EGAD00001001887 82
EGAD00010000869 Illumina_HumanHT-12v4 62
EGAD00010000870 Illumina_Infinium_HumanMethylation450 48
Publications Citations
Integrated genomic characterization of IDH1-mutant glioma malignant progression.
Nat Genet 48: 2016 59-66
Models of epigenetic age capture patterns of DNA methylation in glioma associated with molecular subtype, survival, and recurrence.
Neuro Oncol 20: 2018 942-953
Haploinsufficiency of NFKBIA reshapes the epigenome antipodal to the IDH mutation and imparts disease fate in diffuse gliomas.
Cell Rep Med 4: 2023 101082