Recurrent somatic mutations in POLR2A define a distinct subset of meningiomas

Victoria E. Clark, Akdes Serin Harmancl, Hanwen Bai, Mark W. Youngblood, Tong Ihn Lee, Jacob F. Baranoski, A. Gulhan Ercan-Sencicek, Brian J. Abraham, Abraham S. Weintraub, Denes Hnisz, Matthias Simon, Boris Krischek, E. Zeynep Erson-Omay, Octavian Henegariu, Geneive Carrión-Grant, Ketu Mishra-Gorur, Daniel Durán, Johanna E. Goldmann, Johannes Schramm, Roland GoldbrunnerJoseph M. Piepmeier, Alexander Vortmeyer, Jennifer Moliterno Günel, Kaya Bilgüvar, Katsuhito Yasuno, Richard A. Young, Murat Günel

Research output: Contribution to journalArticle

68 Citations (Scopus)

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, including WNT6 and ZIC1/ZIC4. In addition to mutations in POLR2A, NF2, SMARCB1, TRAF7, KLF4, AKT1, PIK3CA, and SMO, 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.

Original languageEnglish (US)
Pages (from-to)1253-1259
Number of pages7
JournalNature genetics
Volume48
Issue number10
DOIs
StatePublished - Oct 1 2016
Externally publishedYes

Fingerprint

Meningioma
Mutation
RNA Polymerase II
Catalytic RNA
Eukaryotic Cells
Enzymes
Cell Biology
Catalytic Domain
Neoplasms
Carcinogenesis
Pathology
Genes
Proteins

ASJC Scopus subject areas

  • Genetics

Cite this

Clark, V. E., Harmancl, A. S., Bai, H., Youngblood, M. W., Lee, T. I., Baranoski, J. F., ... Günel, M. (2016). Recurrent somatic mutations in POLR2A define a distinct subset of meningiomas. Nature genetics, 48(10), 1253-1259. https://doi.org/10.1038/ng.3651

Recurrent somatic mutations in POLR2A define a distinct subset of meningiomas. / Clark, Victoria E.; Harmancl, 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; Simon, Matthias; Krischek, Boris; Erson-Omay, E. Zeynep; Henegariu, Octavian; Carrión-Grant, Geneive; Mishra-Gorur, Ketu; Durán, Daniel; Goldmann, Johanna E.; Schramm, Johannes; Goldbrunner, Roland; Piepmeier, Joseph M.; Vortmeyer, Alexander; Günel, Jennifer Moliterno; Bilgüvar, Kaya; Yasuno, Katsuhito; Young, Richard A.; Günel, Murat.

In: Nature genetics, Vol. 48, No. 10, 01.10.2016, p. 1253-1259.

Research output: Contribution to journalArticle

Clark, VE, Harmancl, AS, Bai, H, Youngblood, MW, Lee, TI, Baranoski, JF, Ercan-Sencicek, AG, Abraham, BJ, Weintraub, AS, Hnisz, D, Simon, M, Krischek, B, Erson-Omay, EZ, Henegariu, O, Carrión-Grant, G, Mishra-Gorur, K, Durán, D, Goldmann, JE, Schramm, J, Goldbrunner, R, Piepmeier, JM, Vortmeyer, A, Günel, JM, Bilgüvar, K, Yasuno, K, Young, RA & Günel, M 2016, 'Recurrent somatic mutations in POLR2A define a distinct subset of meningiomas', Nature genetics, vol. 48, no. 10, pp. 1253-1259. https://doi.org/10.1038/ng.3651
Clark VE, Harmancl AS, Bai H, Youngblood MW, Lee TI, Baranoski JF et al. Recurrent somatic mutations in POLR2A define a distinct subset of meningiomas. Nature genetics. 2016 Oct 1;48(10):1253-1259. https://doi.org/10.1038/ng.3651
Clark, Victoria E. ; Harmancl, 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 ; Simon, Matthias ; Krischek, Boris ; Erson-Omay, E. Zeynep ; Henegariu, Octavian ; Carrión-Grant, Geneive ; Mishra-Gorur, Ketu ; Durán, Daniel ; Goldmann, Johanna E. ; Schramm, Johannes ; Goldbrunner, Roland ; Piepmeier, Joseph M. ; Vortmeyer, Alexander ; Günel, Jennifer Moliterno ; Bilgüvar, Kaya ; Yasuno, Katsuhito ; Young, Richard A. ; Günel, Murat. / Recurrent somatic mutations in POLR2A define a distinct subset of meningiomas. In: Nature genetics. 2016 ; Vol. 48, No. 10. pp. 1253-1259.
@article{5c05c839c08e454eb6166119f6744d80,
title = "Recurrent somatic mutations in POLR2A define a distinct subset of meningiomas",
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, including WNT6 and ZIC1/ZIC4. In addition to mutations in POLR2A, NF2, SMARCB1, TRAF7, KLF4, AKT1, PIK3CA, and SMO, 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.",
author = "Clark, {Victoria E.} and Harmancl, {Akdes Serin} and Hanwen Bai and Youngblood, {Mark W.} and Lee, {Tong Ihn} and Baranoski, {Jacob F.} and Ercan-Sencicek, {A. Gulhan} and Abraham, {Brian J.} and Weintraub, {Abraham S.} and Denes Hnisz and Matthias Simon and Boris Krischek and Erson-Omay, {E. Zeynep} and Octavian Henegariu and Geneive Carri{\'o}n-Grant and Ketu Mishra-Gorur and Daniel Dur{\'a}n and Goldmann, {Johanna E.} and Johannes Schramm and Roland Goldbrunner and Piepmeier, {Joseph M.} and Alexander Vortmeyer and G{\"u}nel, {Jennifer Moliterno} and Kaya Bilg{\"u}var and Katsuhito Yasuno and Young, {Richard A.} and Murat G{\"u}nel",
year = "2016",
month = "10",
day = "1",
doi = "10.1038/ng.3651",
language = "English (US)",
volume = "48",
pages = "1253--1259",
journal = "Nature Genetics",
issn = "1061-4036",
publisher = "Nature Publishing Group",
number = "10",

}

TY - JOUR

T1 - Recurrent somatic mutations in POLR2A define a distinct subset of meningiomas

AU - Clark, Victoria E.

AU - Harmancl, Akdes Serin

AU - Bai, Hanwen

AU - Youngblood, Mark W.

AU - Lee, Tong Ihn

AU - Baranoski, Jacob F.

AU - Ercan-Sencicek, A. Gulhan

AU - Abraham, Brian J.

AU - Weintraub, Abraham S.

AU - Hnisz, Denes

AU - Simon, Matthias

AU - Krischek, Boris

AU - Erson-Omay, E. Zeynep

AU - Henegariu, Octavian

AU - Carrión-Grant, Geneive

AU - Mishra-Gorur, Ketu

AU - Durán, Daniel

AU - Goldmann, Johanna E.

AU - Schramm, Johannes

AU - Goldbrunner, Roland

AU - Piepmeier, Joseph M.

AU - Vortmeyer, Alexander

AU - Günel, Jennifer Moliterno

AU - Bilgüvar, Kaya

AU - Yasuno, Katsuhito

AU - Young, Richard A.

AU - Günel, Murat

PY - 2016/10/1

Y1 - 2016/10/1

N2 - 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, including WNT6 and ZIC1/ZIC4. In addition to mutations in POLR2A, NF2, SMARCB1, TRAF7, KLF4, AKT1, PIK3CA, and SMO, 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.

AB - 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, including WNT6 and ZIC1/ZIC4. In addition to mutations in POLR2A, NF2, SMARCB1, TRAF7, KLF4, AKT1, PIK3CA, and SMO, 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.

UR - http://www.scopus.com/inward/record.url?scp=84983479137&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84983479137&partnerID=8YFLogxK

U2 - 10.1038/ng.3651

DO - 10.1038/ng.3651

M3 - Article

C2 - 27548314

AN - SCOPUS:84983479137

VL - 48

SP - 1253

EP - 1259

JO - Nature Genetics

JF - Nature Genetics

SN - 1061-4036

IS - 10

ER -