Journal Article

Recurrent somatic mutations in POLR2A define a distinct subset of meningiomas

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

2016

Overview

Murat Günel and colleagues identify recurrent mutations in POLR2A , which encodes the catalytic subunit of RNA polymerase II, in a subset of meningiomas. They find that POLR2A -mutant tumors can be distinguished on the basis of their super-enhancer and gene expression profiles, which show dysregulation of key meningeal identity genes. 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 2 , 3 , including WNT6 and ZIC1 / ZIC4 . In addition to mutations in POLR2A , NF2 , SMARCB1, TRAF7 , KLF4 , AKT1 , PIK3CA , and SMO 4 , 5 , 6 , 7 , 8 , 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.

• Publisher: Nature Publishing Group US,Nature Publishing Group
• Subject: 45/23 / 45/47 / 45/91 / 631/208/212/2166 / 631/67/395 / 692/308/2056 / 692/699/67/395 / Agriculture / Analysis / Animal Genetics and Genomics / Biomedicine / Cancer Research / Catalytic Domain - genetics / Cells (Biology) / Chromosomes, Human, Pair 22 / Cohort Studies / DNA Mutational Analysis / Enhancer Elements, Genetic / Enzymes / Exome / Experiments / Gene expression / Gene Expression Regulation, Neoplastic / Gene Function / Genes / Genetic aspects / Genetic research / Genomes / Genotype / Human Genetics / Humans / Kruppel-Like Transcription Factors - genetics / letter / Meningeal Neoplasms - classification / Meningeal Neoplasms - genetics / Meningioma - classification / Meningioma - genetics / Mutation / Neurofibromin 2 - genetics / RNA / RNA polymerase / RNA Polymerase II - genetics / Stem cells / Transcription (Genetics) / Tumor Necrosis Factor Receptor-Associated Peptides and Proteins - genetics / Tumors