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000143626 1001_ $$0P:(DE-He78)4a8b73f9f05542860120bb0e19527fd2$$aParamasivam, Nagarajan$$b0$$eFirst author
000143626 245__ $$aMutational patterns and regulatory networks in epigenetic subgroups of meningioma.
000143626 260__ $$aHeidelberg$$bSpringer$$c2019
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000143626 520__ $$aDNA 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.
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000143626 7001_ $$00000-0002-6041-7049$$aHübschmann, Daniel$$b1$$eFirst author
000143626 7001_ $$0P:(DE-He78)cd8295952c28dc5b483b5ba9386a5669$$aToprak, Umut H$$b2
000143626 7001_ $$0P:(DE-He78)4096eeffdfc73b75e8ba63dc621a017d$$aIshaque, Naveed$$b3
000143626 7001_ $$aNeidert, Marian$$b4
000143626 7001_ $$0P:(DE-He78)e54a1e0999c1d8c95869ef9188b794cc$$aSchrimpf, Daniel$$b5
000143626 7001_ $$0P:(DE-He78)d20d08adc992abdb6ccffa1686f1ba17$$aStichel, Damian$$b6
000143626 7001_ $$0P:(DE-HGF)0$$aReuss, David$$b7
000143626 7001_ $$0P:(DE-HGF)0$$aSievers, Philipp$$b8
000143626 7001_ $$0P:(DE-HGF)0$$aReinhardt, Annekathrin$$b9
000143626 7001_ $$0P:(DE-HGF)0$$aWefers, Annika K$$b10
000143626 7001_ $$0P:(DE-He78)551bb92841f634070997aa168d818492$$aJones, David T W$$b11
000143626 7001_ $$0P:(DE-He78)73316f3cd41c27508dbb6f4c5e7e7a8a$$aGu, Zuguang$$b12
000143626 7001_ $$0P:(DE-He78)d34d1ebad7bad077f415566344509f0c$$aWerner, Johannes$$b13
000143626 7001_ $$0P:(DE-He78)a8e85c1bd89741ab0c2a28032ba81359$$aUhrig, Sebastian$$b14
000143626 7001_ $$aWirsching, Hans-Georg$$b15
000143626 7001_ $$0P:(DE-He78)c954da35a243d177fdc4a3924f4f8a5c$$aSchick, Matthias$$b16
000143626 7001_ $$0P:(DE-He78)7999346780553d7fab7ba69d5afdfa71$$aBewerunge-Hudler, Melanie$$b17
000143626 7001_ $$0P:(DE-He78)f6b238ac374345c55706521c4f435779$$aBeck, Katja$$b18
000143626 7001_ $$aBrehmer, Stephanie$$b19
000143626 7001_ $$aUrbschat, Steffi$$b20
000143626 7001_ $$aSeiz-Rosenhagen, Marcel$$b21
000143626 7001_ $$aHänggi, Daniel$$b22
000143626 7001_ $$aHerold-Mende, Christel$$b23
000143626 7001_ $$aKetter, Ralf$$b24
000143626 7001_ $$0P:(DE-He78)78b6aa82148e60b4d91e3a37a6d3d9a0$$aEils, Roland$$b25
000143626 7001_ $$aRam, Zvi$$b26
000143626 7001_ $$0P:(DE-He78)f746aa965c4e1af518b016de3aaff5d9$$aPfister, Stefan M$$b27
000143626 7001_ $$0P:(DE-He78)92e9783ca7025f36ce14e12cd348d2ee$$aWick, Wolfgang$$b28
000143626 7001_ $$aWeller, Michael$$b29
000143626 7001_ $$aGrossmann, Rachel$$b30
000143626 7001_ $$0P:(DE-He78)a8a10626a848d31e70cfd96a133cc144$$avon Deimling, Andreas$$b31
000143626 7001_ $$0P:(DE-He78)f2a782242acf94a3114d75c45dc75b37$$aSchlesner, Matthias$$b32$$eLast author
000143626 7001_ $$0P:(DE-He78)a1f4b408b9155beb2a8f7cba4d04fe88$$aSahm, Felix$$b33$$eLast author
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