EGAGenomicsOtherhttps://ega-archive.org/studies/EGAS00001003481EGAEGA study EGAS00001003481Whole Genome Sequencing data for epigenetic subgroups of meningiomaChIPseq Sequencing data for epigenetic subgroups of meningiomarestrictedEGADNA methylation patterns delineate clinically relevant subgroups of meningioma. We previously established the six meningioma methylation classes (MC) benign 1-3, intermediate A and B, and malignant. Here, we set out to identify subgroup-specific mutational patterns and gene regulation. Whole genome sequencing was performed on 62 samples across all MCs and WHO grades from 62 patients with matched blood control, including 40 sporadic meningiomas and 22 meningiomas arising after radiation (Mrad). RNA sequencing was added for 18 of these cases and chromatin-immunoprecipitation for histone H3 lysine 27 acetylation (H3K27ac) followed by sequencing (ChIP-seq) for 16 samples. Besides the known mutations in meningioma, structural variants were found as the mechanism of NF2 inactivation in a small subset (5%) of sporadic meningiomas, similar to previous reports for Mrad. Aberrations of DMD were found to be enriched in MCs with NF2 mutations, and DMD was among the most differentially upregulated genes in NF2 mutant compared to NF2 wild-type cases. The mutational signature AC3, which has been associated with defects in homologous recombination repair (HRR), was detected in both sporadic meningioma and Mrad, but widely distributed across the genome in sporadic cases and enriched near genomic breakpoints in Mrad. Compared to the other MCs, the number of single nucleotide variants matching the AC3 pattern was significantly higher in the malignant MC, which also exhibited higher genomic instability, determined by the numbers of both large segments affected by copy number alterations and breakpoints between large segments. ChIP-seq analysis for H3K27ac revealed a specific activation of genes regulated by the transcription factor FOXM1 in the malignant MC. This analysis also revealed a super enhancer near the HOXD gene cluster in this MC, which, together with general upregulation of HOX genes in the malignant MC, indicates a role of HOX genes in meningioma aggressiveness. This data elucidates the biological mechanisms rendering different epigenetic subgroups of meningiomas, and suggests leveraging HRR as a novel therapeutic target.Mutational patterns and regulatory networks in epigenetic subgroups of meningioma.Paramasivam Nagarajan N, Hübschmann Daniel D, Toprak Umut H UH, Ishaque Naveed N, Neidert Marian M, Schrimpf Daniel D, Stichel Damian D, Reuss David D, Sievers Philipp P, Reinhardt Annekathrin A, Wefers Annika K AK, Jones David T W DTW, Gu Zuguang Z, Werner Johannes J, Uhrig Sebastian S, Wirsching Hans-Georg HG, Schick Matthias M, Bewerunge-Hudler Melanie M, Beck Katja K, Brehmer Stephanie S, Urbschat Steffi S, Seiz-Rosenhagen Marcel M, Hänggi Daniel D, Herold-Mende Christel C, Ketter Ralf R, Eils Roland R, Ram Zvi Z, Pfister Stefan M SM, Wick Wolfgang W, Weller Michael M, Grossmann Rachel R, von Deimling Andreas A, Schlesner Matthias M, Sahm Felix FClear Cell, Parasagittal Meningioma, Intracranial Meningiomas, Sphenoid Wing Meningioma, Intraorbital, Hemangiopericytic, Wing Meningioma, intracranial meningioma, Angiomatous Meningiomas, Multiple Meningiomas, Multiple Meningioma, Cerebral Convexity Meningioma, supratentorial meningioma, Malignant, Microcystic, Sphenoid Wing Meningiomas, Sphenoid, Papillary Meningiomas, Angioblastic, Papillary Meningioma, Sphenoid Wing, Xanthomatous Meningioma, Secretory Meningiomas, Hemangioblastic Meningiomas, Olfactory Groove, Cerebral, Xanthomatous Meningiomas, Fibrous, Secretory Meningioma, Angioblastic Meningioma, Convexity Meningioma, primary meningeal tumor, Fibrous Meningiomas, primary meningeal tumour, Hemangioblastic, Posterior Fossa Meningioma, Clear Cell Meningioma, Transitional Meningiomas, Groove Meningiomas, Epigenomic, Meningotheliomatous, Angiomatous Meningioma, Olfactory, Hemangiopericytic Meningioma, Xanthomatous, Microcystic Meningioma, Meningiomatoses, Olfactory Groove Meningiomas, Secretory, Intraorbital Meningiomas, Meningioma, Posterior Fossa, Transitional, 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bilateral, SGCG_HUMAN, Chromatin Immuno-precipitation, Multiple Meningiomas, Gene, Assay for Transposase-Accessible Chromatin Using Sequencing, neurofibromatosis, Malignant, HSMCSGEN1, presence, Microcystic, TYPE, PHAPII, froggy, Gyltl1a, DAGA4, Wieacker Wolff syndrome, Stability, reduced, Sphenoid Wing, Instabilities, Xanthomatous Meningioma, Chromatin Immunoprecipitation Sequencing-Chip, 35DAG, neurofibromatosis type II, intellectual disability-developmental delay-contractures syndrome, Secretory Meningiomas, tiny, Hemangioblastic Meningiomas, Olfactory Groove, Cerebral, SCG3, acoustic neurinoma, Secretory Meningioma, Genetic, pattern, distribution, Chromatin Immunoprecipitation Paired End Tag, ipp2a2, Acetylations, LARGE, Groove Meningiomas, bilateral, inter-organelle junction, Duchenne type, BPFD#36, Olfactory, RNA Sequence Analyses, taf-ibeta, Clients, Microcystic Meningioma, RNA Sequencing, Rhp51-dependent recombinational repair, Wieacker syndrome, Family, Posterior Fossa, 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dSET/TAF-Ibeta, Wing Meningiomas, susceptibility to familial meningioma, 2610030F17Rik, RNA Sequence Analysis, SCARMD2, cardinality, Spinal, H3(any), assay, AA407739, 6-diaminohexanoic acid, SCH, Genome, glycosyltransferase-like protein LARGE1falseMutational patterns and regulatory networks in epigenetic subgroups of meningioma (H033)DNA methylation patterns delineate clinically relevant subgroups of meningioma. We previously established the six meningioma methylation classes (MC) benign-1, 2, 3, intermediate-A, B and malignant. Here, we set out to identify subgroup-specific mutational patterns and pathway regulation. Whole-genome-sequencing was performed on 62 samples across all MCs and WHO grades from 62 patients with matched blood control, including 40 sporadic and 22 radiation-induced (Mrad) meningiomas. RNA sequencing was added for 18 cases and chromatin-immunoprecipitation for the enhancer mark H3K27ac followed by sequencing (ChIP-seq) for 16 samples. Besides the known mutations in meningioma, structural alterations were found to contribute to the spectrum of mechanisms inactivating NF2 in sporadic meningioma similar to previous reports for Mrad. Aberrations of DMD were found to be enriched in MCs with NF2 mutations and DMD was among the most differentially upregulated genes in NF2 mutant compared to NF2 wild-type cases. The mutational signature AC3 was detected in both sporadic meningioma and Mrad, but distributed across the genome in sporadic cases and enriched near genomic breakpoints in Mrad. In general, the malignant MC presented a significantly higher exposure to AC3 and higher genomic instability beyond the mutational load than the other MCs. Pathway analysis of the ChIP-seq clusters revealed that the FOXM1 is most differentially activated in high-grade cases, along with super enhancer recruitment near HOX genes and respective upregulation of expression. This data further elucidate the biological mechanisms differentiating meningiomas of different WHO grade and epigenetic subgroups and suggest leveraging the genomic instability as novel therapeutic targets.2019-06-12 09:53:14EGAS00001003481960631069492EGAD00001005021EGAD00001005061EGAC00001000219EGAC00001000452