Recurrent somatic mutations in POLR2A define a distinct subset of meningiomas [ChIP-seq]

RNA polymerase II mediates the transcription of all protein-coding genes in eukaryotic cells, a process that is fundamental to life. Genomic mutations in this enzyme have not been previously linked to any pathology in humans, a testament to its indispensable role in cell biology. Based on 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, are sufficient to hijack this essential enzyme and drive neoplasia. POLR2A mutant tumors reveal dysregulation of key meningeal identity genes, including WNT6 and ZIC1/ZIC4. In addition to 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. Overall design: Peak calls from H3K27ac ChIPseq data from 22 samples, including 20 tumors representing the major mutation groups (NF2/chr22 loss, POLR2A, KLF4/TRAF7, PI3K mutant, Sonic Hedgehog mutant) and 2 control samples (dura). The H3k27ac ChIP-seq data for 14 benign meningiomas and 2 dura samples listed below were created by Dr. Justin Cotney in Dr. James Noonan's lab at Yale and previously published in a paper by our group with Drs. Cotney and Noonan as co-authors (Clark et al. Science, 2013). Sample IDs: MN-297, MN-288, MN-163, MN-1037, MN-105, MN-201, MN-249, MN-191, MN-1066, MN-169, MN-291, MN-24, MN-79, MN-1044, DURA_1, DURA_2. In this study, we used these meningioma H3k27ac ChIP-seq data as controls and compared them to the newly created ChIP-seq data. Sample IDs: MN-1200, MN-63345, MN-60355, MN-63670, MN-64273, MN-296. This GEO entry contains ChIP-seq results for both data sets.