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 O. Vortmeyer, Jennifer Moliterno Günel, Kaya Bilgüvar, Katsuhito Yasuno, Richard A. Young, Murat Günel

Research output: Contribution to journalArticle

83 Scopus citations

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

ASJC Scopus subject areas

  • Genetics

Fingerprint Dive into the research topics of 'Recurrent somatic mutations in POLR2A define a distinct subset of meningiomas'. Together they form a unique fingerprint.

  • Cite this

    Clark, V. E., Harmancl, A. S., Bai, H., Youngblood, M. W., Lee, T. I., Baranoski, J. F., Ercan-Sencicek, A. G., Abraham, B. J., Weintraub, A. S., Hnisz, D., Simon, M., Krischek, B., Erson-Omay, E. Z., Henegariu, O., Carrión-Grant, G., Mishra-Gorur, K., Durán, D., Goldmann, J. E., Schramm, J., ... 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