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      Recurrent somatic mutations in POLR2A define a distinct subset of meningiomas.

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      Nature genetics

      Springer Science and Business Media LLC

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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, 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.

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          Author and article information

          Journal
          Nat. Genet.
          Nature genetics
          Springer Science and Business Media LLC
          1546-1718
          1061-4036
          October 2016
          : 48
          : 10
          Affiliations
          [1 ] Yale Program in Brain Tumor Research, Yale School of Medicine, New Haven, Connecticut, USA.
          [2 ] Department of Neurosurgery, Yale School of Medicine, New Haven, Connecticut, USA.
          [3 ] Department of Genetics, Yale School of Medicine, New Haven, Connecticut, USA.
          [4 ] Whitehead Institute for Biomedical Research, Cambridge, Massachusetts, USA.
          [5 ] Yale Program on Neurogenetics, Yale School of Medicine, New Haven, Connecticut, USA.
          [6 ] Department of Neurosurgery, University of Bonn Medical School, Bonn, Germany.
          [7 ] Department of General Neurosurgery, University Hospital of Cologne, Cologne, Germany.
          [8 ] Department of Neuroscience, Yale School of Medicine, New Haven, Connecticut, USA.
          [9 ] Medical Faculty, University of Bonn Medical School, Bonn, Germany.
          [10 ] Department of Pathology, Yale School of Medicine, New Haven, Connecticut, USA.
          [11 ] Yale Center for Genome Analysis, Yale School of Medicine, Orange, Connecticut, USA.
          [12 ] Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.
          [13 ] Yale Comprehensive Cancer Center, Yale School of Medicine, New Haven, Connecticut, USA.
          Article
          ng.3651 NIHMS826984
          10.1038/ng.3651
          5114141
          27548314

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