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.

Type: Other
Archiver: EGA European Genome-Phenome Archive

3 Datasets 3 Publications

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	Exome sequencing VCF files describing mutations during glioma progression.		82
EGAD00010000869	RNA expression microarray	Illumina_HumanHT-12v4	62
EGAD00010000870	DNA methylation microarray	Illumina_Infinium_HumanMethylation450	48

Publications	Citations
Integrated genomic characterization of IDH1-mutant glioma malignant progression. Bai H, Harmancı AS, Erson-Omay EZ, Li J, Coşkun S, Simon M, Krischek B, Özduman K, Omay SB, Sorensen EA, Turcan Ş, Bakırcığlu M, Carrión-Grant G, Murray PB, Clark VE, Ercan-Sencicek AG, Knight J, Sencar L, Altınok S, Kaulen LD, Gülez B, Timmer M, Schramm J, Mishra-Gorur K, Henegariu O, Moliterno J, Louvi A, Chan TA, Tannheimer SL, Pamir MN, Vortmeyer AO, Bilguvar K, Yasuno K, Günel M. Nat Genet 48: 2016 59-66	158
Models of epigenetic age capture patterns of DNA methylation in glioma associated with molecular subtype, survival, and recurrence. Liao P, Ostrom QT, Stetson L, Barnholtz-Sloan JS. Neuro Oncol 20: 2018 942-953	19
Haploinsufficiency of NFKBIA reshapes the epigenome antipodal to the IDH mutation and imparts disease fate in diffuse gliomas. Bredel M, Espinosa L, Kim H, Scholtens DM, McElroy JP, Rajbhandari R, Meng W, Kollmeyer TM, Malta TM, Quezada MA, Harsh GR, Lobo-Jarne T, Solé L, Merati A, Nagaraja S, Nair S, White JJ, Thudi NK, Fleming JL, Webb A, Natsume A, Ogawa S, Weber RG, Bertran J, Haque SJ, Hentschel B, Miller CR, Furnari FB, Chan TA, Grosu AL, Weller M, Barnholtz-Sloan JS, Monje M, Noushmehr H, Jenkins RB, Rogers CL, MacDonald DR, Pugh SL, Chakravarti A. Cell Rep Med 4: 2023 101082	0