Clarke, Victoria E., Harmanci, Akdes Serin, Bai, Hanwen, Youngblood, Mark W., Lee, Tong Ihn, Baranoski, Jacob F., Ercan-Sencicek, A. Gulhan, Abraham, Brian J., Weintraub, Abraham S., Hnisz, Denes ORCID: 0000-0002-6256-1693, Simon, Matthias, Krischek, Boris, Erson-Omay, E. Zeynep, Henegariu, Octavian, Carrion-Grant, Geneive, Mishra-Gorur, Ketu, Duran, Daniel ORCID: 0000-0001-6888-252X, Goldmann, Johanna E., Schramm, Johannes, Goldbrunner, Roland, Piepmeier, Joseph M., Vortmeyer, Alexander O., Gunel, Jennifer Molitemo, Bilguvar, Kaya, Yasuno, Katsuhito ORCID: 0000-0002-3606-532X, Young, Richard A. and Gunel, Murat (2016). Recurrent somatic mutations in POLR2A define a distinct subset of meningiomas. Nature Genet., 48 (10). S. 1253 - 1260. NEW YORK: NATURE PUBLISHING GROUP. ISSN 1546-1718

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Abstract

RNA polymerase II mediates the transcription of all protein-coding genes in eukaryotic cells, a process that is fundamental to life. Genomic mutations altering this enzyme have not previously been linked to any pathology in humans, which is a testament to its indispensable role in cell biology. On the basis of a combination of next-generation genomic analyses of 775 meningiomas, we report that recurrent somatic p.Gln403Lys or p.Leu438_His439del mutations in POLR2A, which encodes the catalytic subunit of RNA polymerase II (ref. 1), hijack this essential enzyme and drive neoplasia. POLR2A mutant tumors show dysregulation of key meningeal identity genes(2,3), including WNT6 and ZIC1/ZIC4. In addition to mutations in POLR2A, NF2, SMARCB1,TRAF7, KLF4, AKT1, PIK3CA, and SMO4-8, we also report somatic mutations in AKT3, PIK3R1, PRKAR1A, and SUFU in meningiomas. Our results identify a role for essential transcriptional machinery in driving tumorigenesis and define mutually exclusive meningioma subgroups with distinct clinical and pathological features.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Clarke, Victoria E.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Harmanci, Akdes SerinUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bai, HanwenUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Youngblood, Mark W.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lee, Tong IhnUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Baranoski, Jacob F.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ercan-Sencicek, A. GulhanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Abraham, Brian J.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Weintraub, Abraham S.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hnisz, DenesUNSPECIFIEDorcid.org/0000-0002-6256-1693UNSPECIFIED
Simon, MatthiasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Krischek, BorisUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Erson-Omay, E. ZeynepUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Henegariu, OctavianUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Carrion-Grant, GeneiveUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Mishra-Gorur, KetuUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Duran, DanielUNSPECIFIEDorcid.org/0000-0001-6888-252XUNSPECIFIED
Goldmann, Johanna E.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schramm, JohannesUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Goldbrunner, RolandUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Piepmeier, Joseph M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Vortmeyer, Alexander O.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Gunel, Jennifer MolitemoUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bilguvar, KayaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Yasuno, KatsuhitoUNSPECIFIEDorcid.org/0000-0002-3606-532XUNSPECIFIED
Young, Richard A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Gunel, MuratUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-260967
DOI: 10.1038/ng.3651
Journal or Publication Title: Nature Genet.
Volume: 48
Number: 10
Page Range: S. 1253 - 1260
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
TRANSCRIPTION FACTORS; SUPER-ENHANCERS; CELL IDENTITY; AKT1; TRAF7; KLF4; SMOMultiple languages
Genetics & HeredityMultiple languages
Refereed: Yes
URI: http://kups.ub.uni-koeln.de/id/eprint/26096

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