Bai, Hanwen, Harmanci, Akdes Serin, Erson-Omay, E. Zeynep, Li, Jie, Coskun, Sueleyman, Simon, Matthias, Krischek, Boris, Ozduman, Koray ORCID: 0000-0002-3543-0401, Omay, S. Buelent, Sorensen, Eric A., Turcan, Sevin ORCID: 0000-0002-0885-5607, Bakirciglu, Mehmet, Carrion-Grant, Geneive, Murray, Phillip B., Clark, Victoria E., Ercan-Sencicek, A. Gulhan, Knight, James, Sencar, Leman, Altinok, Selin, Kaulen, Leon D., Guelez, Burcu, Timmer, Marco, Schramm, Johannes, Mishra-Gorur, Ketu, Henegariu, Octavian, Moliterno, Jennifer, Louvi, Angeliki, Chan, Timothy A., Tannheimer, Stacey L., Pamir, M. Necmettin, Vortmeyer, Alexander O., Bilguvar, Kaya, Yasuno, Katsuhito ORCID: 0000-0002-3606-532X and Guenel, Murat (2016). Integrated genomic characterization of IDH1-mutant glioma malignant progression. Nature Genet., 48 (1). S. 59 - 70. NEW YORK: NATURE PUBLISHING GROUP. ISSN 1546-1718

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Abstract

Gliomas represent approximately 30% of all central nervous system tumors and 80% of malignant brain tumors(1). 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.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Bai, HanwenUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Harmanci, Akdes SerinUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Erson-Omay, E. ZeynepUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Li, JieUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Coskun, SueleymanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Simon, MatthiasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Krischek, BorisUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ozduman, KorayUNSPECIFIEDorcid.org/0000-0002-3543-0401UNSPECIFIED
Omay, S. BuelentUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Sorensen, Eric A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Turcan, SevinUNSPECIFIEDorcid.org/0000-0002-0885-5607UNSPECIFIED
Bakirciglu, MehmetUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Carrion-Grant, GeneiveUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Murray, Phillip B.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Clark, Victoria E.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ercan-Sencicek, A. GulhanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Knight, JamesUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Sencar, LemanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Altinok, SelinUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kaulen, Leon D.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Guelez, BurcuUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Timmer, MarcoUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schramm, JohannesUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Mishra-Gorur, KetuUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Henegariu, OctavianUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Moliterno, JenniferUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Louvi, AngelikiUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Chan, Timothy A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Tannheimer, Stacey L.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Pamir, M. NecmettinUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Vortmeyer, Alexander O.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bilguvar, KayaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Yasuno, KatsuhitoUNSPECIFIEDorcid.org/0000-0002-3606-532XUNSPECIFIED
Guenel, MuratUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-293145
DOI: 10.1038/ng.3457
Journal or Publication Title: Nature Genet.
Volume: 48
Number: 1
Page Range: S. 59 - 70
Date: 2016
Publisher: NATURE PUBLISHING GROUP
Place of Publication: NEW YORK
ISSN: 1546-1718
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
GROUP PROTEIN EZH2; MUTATIONAL LANDSCAPE; DNA METHYLATION; ADJUVANT TEMOZOLOMIDE; TRANSCRIPTION FACTORS; SOMATIC MUTATIONS; C-MYC; CANCER; GENE; GLIOBLASTOMAMultiple languages
Genetics & HeredityMultiple languages
Refereed: Yes
URI: http://kups.ub.uni-koeln.de/id/eprint/29314

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