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.
authors.affiliation: Yale 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 Genetics, Yale School of Medicine, New Haven, Connecticut, USA.
authors.forename: Victoria E
authors.initials: VE
authors.lastname: Clark
authors.affiliation: Yale 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: Yale Program in Brain Tumor Research, Yale School of Medicine, New Haven, Connecticut, USA.|Department of Genetics, Yale School of Medicine, New Haven, Connecticut, USA.
authors.forename: Hanwen
authors.identifier: 0000-0002-8473-5279
authors.initials: H
authors.lastname: Bai
authors.affiliation: Yale 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 Genetics, Yale School of Medicine, New Haven, Connecticut, USA.
authors.forename: Mark W
authors.initials: MW
authors.lastname: Youngblood
authors.affiliation: Whitehead Institute for Biomedical Research, Cambridge, Massachusetts, USA.
authors.forename: Tong Ihn
authors.initials: TI
authors.lastname: Lee
authors.affiliation: Yale 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 Genetics, Yale School of Medicine, New Haven, Connecticut, USA.
authors.forename: Jacob F
authors.initials: JF
authors.lastname: Baranoski
authors.affiliation: Department of Neurosurgery, Yale School of Medicine, New Haven, Connecticut, USA.|Yale Program on Neurogenetics, Yale School of Medicine, New Haven, Connecticut, USA.
authors.forename: A Gulhan
authors.initials: AG
authors.lastname: Ercan-Sencicek
authors.affiliation: Whitehead Institute for Biomedical Research, Cambridge, Massachusetts, USA.
authors.forename: Brian J
authors.initials: BJ
authors.lastname: Abraham
authors.affiliation: Whitehead Institute for Biomedical Research, Cambridge, Massachusetts, USA.
authors.forename: Abraham S
authors.initials: AS
authors.lastname: Weintraub
authors.affiliation: Whitehead Institute for Biomedical Research, Cambridge, Massachusetts, USA.
authors.forename: Denes
authors.initials: D
authors.lastname: Hnisz
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: Yale 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: Yale 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 Genetics, Yale School of Medicine, New Haven, Connecticut, USA.|Yale Program on Neurogenetics, Yale School of Medicine, New Haven, Connecticut, USA.|Department of Neuroscience, Yale School of Medicine, New Haven, Connecticut, USA.
authors.forename: Octavian
authors.initials: O
authors.lastname: Henegariu
authors.affiliation: Yale 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: Yale 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 Genetics, Yale School of Medicine, New Haven, Connecticut, USA.|Yale Program on Neurogenetics, Yale School of Medicine, New Haven, Connecticut, USA.|Department of Neuroscience, Yale School of Medicine, New Haven, Connecticut, USA.
authors.forename: Ketu
authors.initials: K
authors.lastname: Mishra-Gorur
authors.affiliation: Yale 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 Genetics, Yale School of Medicine, New Haven, Connecticut, USA.
authors.forename: Daniel
authors.initials: D
authors.lastname: Durán
authors.affiliation: Whitehead Institute for Biomedical Research, Cambridge, Massachusetts, USA.
authors.forename: Johanna E
authors.initials: JE
authors.lastname: Goldmann
authors.affiliation: Medical Faculty, University of Bonn Medical School, Bonn, Germany.
authors.forename: Johannes
authors.initials: J
authors.lastname: Schramm
authors.affiliation: Department of General Neurosurgery, University Hospital of Cologne, Cologne, Germany.
authors.forename: Roland
authors.initials: R
authors.lastname: Goldbrunner
authors.affiliation: Department of Neurosurgery, Yale School of Medicine, New Haven, Connecticut, USA.
authors.forename: Joseph M
authors.initials: JM
authors.lastname: Piepmeier
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: Yale 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 Moliterno
authors.initials: JM
authors.lastname: Günel
authors.affiliation: Yale Program in Brain Tumor Research, Yale School of Medicine, New Haven, Connecticut, USA.|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: Kaya
authors.initials: K
authors.lastname: Bilgüvar
authors.affiliation: Yale 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: 0000-0002-3606-532X
authors.initials: K
authors.lastname: Yasuno
authors.affiliation: Whitehead Institute for Biomedical Research, Cambridge, Massachusetts, USA.|Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.
authors.forename: Richard A
authors.identifier: 0000-0001-8855-8647
authors.initials: RA
authors.lastname: Young
authors.affiliation: Yale 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 Genetics, Yale School of Medicine, New Haven, Connecticut, USA.|Yale Program on Neurogenetics, Yale School of Medicine, New Haven, Connecticut, USA.|Department of Neuroscience, 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: D020134:Catalytic Domain / Q000235:genetics; D002892:Chromosomes, Human, Pair 22; D015331:Cohort Studies; D004252:DNA Mutational Analysis; D004742:Enhancer Elements, Genetic; D059472:Exome; D015972:Gene Expression Regulation, Neoplastic; D005838:Genotype; D006801:Humans; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors / Q000235:genetics; D008577:Meningeal Neoplasms / Q000145:classification / Q000235:genetics*; D008579:Meningioma / Q000145:classification / Q000235:genetics*; D009154:Mutation; D025581:Neurofibromin 2 / Q000235:genetics; D012319:RNA Polymerase II / Q000235:genetics*; D047988:Tumor Necrosis Factor Receptor-Associated Peptides and Proteins / Q000235:genetics
chemical_list: C000715467:KLF4 protein, human; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors; D025581:Neurofibromin 2; C486460:TRAF7 protein, human; D047988:Tumor Necrosis Factor Receptor-Associated Peptides and Proteins; D012319:RNA Polymerase II