Recurrent somatic mutations in POLR2A define a distinct subset of meningiomas

Nat Genet. 2016 Oct;48(10):1253-9. doi: 10.1038/ng.3651. Epub 2016 Aug 22.

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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, N.I.H., Extramural

MeSH terms

  • Catalytic Domain / genetics
  • Chromosomes, Human, Pair 22
  • Cohort Studies
  • DNA Mutational Analysis
  • Enhancer Elements, Genetic
  • Exome
  • Gene Expression Regulation, Neoplastic
  • Genotype
  • Humans
  • Kruppel-Like Transcription Factors / genetics
  • Meningeal Neoplasms / classification
  • Meningeal Neoplasms / genetics*
  • Meningioma / classification
  • Meningioma / genetics*
  • Mutation*
  • Neurofibromin 2 / genetics
  • RNA Polymerase II / genetics*
  • Tumor Necrosis Factor Receptor-Associated Peptides and Proteins / genetics

Substances

  • GKLF protein
  • Kruppel-Like Transcription Factors
  • Neurofibromin 2
  • TRAF7 protein, human
  • Tumor Necrosis Factor Receptor-Associated Peptides and Proteins
  • RNA Polymerase II