title: Integrated genomic characterization of IDH1-mutant glioma malignant progression.
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.
authors.affiliation: Department of Genetics, Yale School of Medicine, New Haven, Connecticut, USA.|Program in Brain Tumor Research, Yale School of Medicine, New Haven, Connecticut, USA.
authors.forename: Hanwen
authors.initials: H
authors.lastname: Bai
authors.affiliation: Program in Brain Tumor Research, Yale School of Medicine, New Haven, Connecticut, USA.|Department of Neurosurgery, Yale School of Medicine, New Haven, Connecticut, USA.
authors.forename: Akdes Serin
authors.initials: AS
authors.lastname: Harmancı
authors.affiliation: Program in Brain Tumor Research, Yale School of Medicine, New Haven, Connecticut, USA.|Department of Neurosurgery, Yale School of Medicine, New Haven, Connecticut, USA.
authors.forename: E Zeynep
authors.initials: EZ
authors.lastname: Erson-Omay
authors.affiliation: Department of Pathology, Yale School of Medicine, New Haven, Connecticut, USA.
authors.forename: Jie
authors.initials: J
authors.lastname: Li
authors.affiliation: Program in Brain Tumor Research, Yale School of Medicine, New Haven, Connecticut, USA.|Department of Neurosurgery, Yale School of Medicine, New Haven, Connecticut, USA.
authors.forename: Süleyman
authors.initials: S
authors.lastname: Coşkun
authors.affiliation: Department of Neurosurgery, University of Bonn Medical School, Bonn, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Simon
authors.affiliation: Department of General Neurosurgery, University Hospital of Cologne, Cologne, Germany.
authors.forename: Boris
authors.initials: B
authors.lastname: Krischek
authors.affiliation: Department of Neurosurgery, Acıbadem University School of Medicine, Istanbul, Turkey.
authors.forename: Koray
authors.initials: K
authors.lastname: Özduman
authors.affiliation: Program in Brain Tumor Research, Yale School of Medicine, New Haven, Connecticut, USA.|Department of Neurosurgery, Yale School of Medicine, New Haven, Connecticut, USA.
authors.forename: S Bülent
authors.initials: SB
authors.lastname: Omay
authors.affiliation: Translational Medicine, Biomarkers, Gilead Sciences, Inc., Foster City, California, USA.
authors.forename: Eric A
authors.initials: EA
authors.lastname: Sorensen
authors.affiliation: Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
authors.forename: Şevin
authors.initials: Ş
authors.lastname: Turcan
authors.affiliation: Department of Neurosurgery, Acıbadem University School of Medicine, Istanbul, Turkey.
authors.forename: Mehmet
authors.initials: M
authors.lastname: Bakırcığlu
authors.affiliation: Program in Brain Tumor Research, Yale School of Medicine, New Haven, Connecticut, USA.|Department of Neurosurgery, Yale School of Medicine, New Haven, Connecticut, USA.
authors.forename: Geneive
authors.initials: G
authors.lastname: Carrión-Grant
authors.affiliation: Department of Pharmacology, Yale School of Medicine, New Haven, Connecticut, USA.
authors.forename: Phillip B
authors.initials: PB
authors.lastname: Murray
authors.affiliation: Department of Genetics, Yale School of Medicine, New Haven, Connecticut, USA.|Program in Brain Tumor Research, Yale School of Medicine, New Haven, Connecticut, USA.|Department of Neurosurgery, Yale School of Medicine, New Haven, Connecticut, USA.
authors.forename: Victoria E
authors.initials: VE
authors.lastname: Clark
authors.affiliation: Program in Brain Tumor Research, Yale School of Medicine, New Haven, Connecticut, USA.|Department of Neurosurgery, Yale School of Medicine, New Haven, Connecticut, USA.
authors.forename: A Gulhan
authors.initials: AG
authors.lastname: Ercan-Sencicek
authors.affiliation: Department of Genetics, Yale School of Medicine, New Haven, Connecticut, USA.|Yale Center for Genome Analysis, Yale School of Medicine, Orange, Connecticut, USA.
authors.forename: James
authors.initials: J
authors.lastname: Knight
authors.affiliation: Program in Brain Tumor Research, Yale School of Medicine, New Haven, Connecticut, USA.|Department of Neurosurgery, Yale School of Medicine, New Haven, Connecticut, USA.
authors.forename: Leman
authors.initials: L
authors.lastname: Sencar
authors.affiliation: Program in Brain Tumor Research, Yale School of Medicine, New Haven, Connecticut, USA.|Department of Neurosurgery, Yale School of Medicine, New Haven, Connecticut, USA.
authors.forename: Selin
authors.initials: S
authors.lastname: Altınok
authors.affiliation: Program in Brain Tumor Research, Yale School of Medicine, New Haven, Connecticut, USA.|Department of Neurosurgery, Yale School of Medicine, New Haven, Connecticut, USA.
authors.forename: Leon D
authors.initials: LD
authors.lastname: Kaulen
authors.affiliation: Program in Brain Tumor Research, Yale School of Medicine, New Haven, Connecticut, USA.|Department of Neurosurgery, Yale School of Medicine, New Haven, Connecticut, USA.
authors.forename: Burcu
authors.initials: B
authors.lastname: Gülez
authors.affiliation: Department of General Neurosurgery, University Hospital of Cologne, Cologne, Germany.
authors.forename: Marco
authors.initials: M
authors.lastname: Timmer
authors.affiliation: Department of Neurosurgery, University of Bonn Medical School, Bonn, Germany.
authors.forename: Johannes
authors.initials: J
authors.lastname: Schramm
authors.affiliation: Department of Genetics, Yale School of Medicine, New Haven, Connecticut, USA.|Program in Brain Tumor Research, Yale School of Medicine, New Haven, Connecticut, USA.|Department of Neurosurgery, Yale School of Medicine, New Haven, Connecticut, USA.|Department of Neurobiology, Yale School of Medicine, New Haven, Connecticut, USA.|Yale Program on Neurogenetics, Yale School of Medicine, New Haven, Connecticut, USA.
authors.forename: Ketu
authors.initials: K
authors.lastname: Mishra-Gorur
authors.affiliation: Department of Genetics, Yale School of Medicine, New Haven, Connecticut, USA.|Program in Brain Tumor Research, Yale School of Medicine, New Haven, Connecticut, USA.|Department of Neurosurgery, Yale School of Medicine, New Haven, Connecticut, USA.|Department of Neurobiology, Yale School of Medicine, New Haven, Connecticut, USA.|Yale Program on Neurogenetics, Yale School of Medicine, New Haven, Connecticut, USA.
authors.forename: Octavian
authors.initials: O
authors.lastname: Henegariu
authors.affiliation: Program in Brain Tumor Research, Yale School of Medicine, New Haven, Connecticut, USA.|Department of Neurosurgery, Yale School of Medicine, New Haven, Connecticut, USA.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Moliterno
authors.affiliation: Department of Neurosurgery, Yale School of Medicine, New Haven, Connecticut, USA.|Department of Neurobiology, Yale School of Medicine, New Haven, Connecticut, USA.|Yale Program on Neurogenetics, Yale School of Medicine, New Haven, Connecticut, USA.
authors.forename: Angeliki
authors.initials: A
authors.lastname: Louvi
authors.affiliation: Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York, USA.|Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
authors.forename: Timothy A
authors.initials: TA
authors.lastname: Chan
authors.affiliation: Translational Medicine, Biomarkers, Gilead Sciences, Inc., Foster City, California, USA.
authors.forename: Stacey L
authors.initials: SL
authors.lastname: Tannheimer
authors.affiliation: Department of Neurosurgery, Acıbadem University School of Medicine, Istanbul, Turkey.
authors.forename: M Necmettin
authors.initials: MN
authors.lastname: Pamir
authors.affiliation: Department of Pathology, Yale School of Medicine, New Haven, Connecticut, USA.
authors.forename: Alexander O
authors.initials: AO
authors.lastname: Vortmeyer
authors.affiliation: Department of Genetics, Yale School of Medicine, New Haven, Connecticut, USA.|Program in Brain Tumor Research, Yale School of Medicine, New Haven, Connecticut, USA.|Yale Center for Genome Analysis, Yale School of Medicine, Orange, Connecticut, USA.|Yale Program on Neurogenetics, Yale School of Medicine, New Haven, Connecticut, USA.
authors.forename: Kaya
authors.initials: K
authors.lastname: Bilguvar
authors.affiliation: Program in Brain Tumor Research, Yale School of Medicine, New Haven, Connecticut, USA.|Department of Neurosurgery, Yale School of Medicine, New Haven, Connecticut, USA.
authors.forename: Katsuhito
authors.identifier: http://orcid.org/0000-0002-3606-532X
authors.initials: K
authors.lastname: Yasuno
authors.affiliation: Department of Genetics, Yale School of Medicine, New Haven, Connecticut, USA.|Program in Brain Tumor Research, Yale School of Medicine, New Haven, Connecticut, USA.|Department of Neurosurgery, Yale School of Medicine, New Haven, Connecticut, USA.|Department of Neurobiology, Yale School of Medicine, New Haven, Connecticut, USA.|Yale Program on Neurogenetics, Yale School of Medicine, New Haven, Connecticut, USA.|Yale Comprehensive Cancer Center, Yale School of Medicine, New Haven, Connecticut, USA.
authors.forename: Murat
authors.initials: M
authors.lastname: Günel
mesh_terms: D016543:Central Nervous System Neoplasms / Q000235:genetics* / Q000473:pathology; D019175:DNA Methylation; D053595:Embryonic Stem Cells / Q000378:metabolism; D000072278:Forkhead Box Protein M1; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism; D018628:Gene Dosage; D015972:Gene Expression Regulation, Neoplastic; D016259:Genes, myc; D005910:Glioma / Q000235:genetics* / Q000473:pathology; D006801:Humans; D007521:Isocitrate Dehydrogenase / Q000235:genetics* / Q000378:metabolism; D009154:Mutation; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism; D051881:Receptor, Notch1 / Q000235:genetics / Q000378:metabolism
chemical_list: C107585:FOXM1 protein, human; D000072278:Forkhead Box Protein M1; D051858:Forkhead Transcription Factors; C497761:NOTCH1 protein, human; D051881:Receptor, Notch1; D007521:Isocitrate Dehydrogenase; C543588:IDH1 protein, human; D019869:Phosphatidylinositol 3-Kinases