Mutational patterns and regulatory networks in epigenetic subgroups of meningioma
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Mutational patterns and regulatory networks in epigenetic subgroups of meningioma. / Paramasivam, Nagarajan; Hübschmann, Daniel; Toprak, Umut H; Ishaque, Naveed; Neidert, Marian; Schrimpf, Daniel; Stichel, Damian; Reuss, David; Sievers, Philipp; Reinhardt, Annekathrin; Wefers, Annika K; Jones, David T W; Gu, Zuguang; Werner, Johannes; Uhrig, Sebastian; Wirsching, Hans-Georg; Schick, Matthias; Bewerunge-Hudler, Melanie; Beck, Katja; Brehmer, Stephanie; Urbschat, Steffi; Seiz-Rosenhagen, Marcel; Hänggi, Daniel; Herold-Mende, Christel; Ketter, Ralf; Eils, Roland; Ram, Zvi; Pfister, Stefan M; Wick, Wolfgang; Weller, Michael; Grossmann, Rachel; von Deimling, Andreas; Schlesner, Matthias; Sahm, Felix.
in: ACTA NEUROPATHOL, Jahrgang 138, Nr. 2, 08.2019, S. 295-308.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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TY - JOUR
T1 - Mutational patterns and regulatory networks in epigenetic subgroups of meningioma
AU - Paramasivam, Nagarajan
AU - Hübschmann, Daniel
AU - Toprak, Umut H
AU - Ishaque, Naveed
AU - Neidert, Marian
AU - Schrimpf, Daniel
AU - Stichel, Damian
AU - Reuss, David
AU - Sievers, Philipp
AU - Reinhardt, Annekathrin
AU - Wefers, Annika K
AU - Jones, David T W
AU - Gu, Zuguang
AU - Werner, Johannes
AU - Uhrig, Sebastian
AU - Wirsching, Hans-Georg
AU - Schick, Matthias
AU - Bewerunge-Hudler, Melanie
AU - Beck, Katja
AU - Brehmer, Stephanie
AU - Urbschat, Steffi
AU - Seiz-Rosenhagen, Marcel
AU - Hänggi, Daniel
AU - Herold-Mende, Christel
AU - Ketter, Ralf
AU - Eils, Roland
AU - Ram, Zvi
AU - Pfister, Stefan M
AU - Wick, Wolfgang
AU - Weller, Michael
AU - Grossmann, Rachel
AU - von Deimling, Andreas
AU - Schlesner, Matthias
AU - Sahm, Felix
PY - 2019/8
Y1 - 2019/8
N2 - DNA 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.
AB - DNA 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.
KW - Chromatin Immunoprecipitation
KW - DNA Methylation
KW - DNA, Neoplasm/genetics
KW - Gene Dosage
KW - Gene Expression Regulation, Neoplastic/genetics
KW - Genomic Instability
KW - Humans
KW - Meningeal Neoplasms/classification
KW - Meningioma/classification
KW - Mutation
KW - Neoplasm Proteins/genetics
KW - Neoplasms, Radiation-Induced/genetics
KW - Polymorphism, Single Nucleotide
KW - RNA, Messenger/genetics
KW - RNA, Neoplasm/genetics
KW - Recombinational DNA Repair
KW - Sequence Alignment
KW - Transcription Factors/physiology
KW - Transcriptome
KW - Whole Genome Sequencing
U2 - 10.1007/s00401-019-02008-w
DO - 10.1007/s00401-019-02008-w
M3 - SCORING: Journal article
C2 - 31069492
VL - 138
SP - 295
EP - 308
JO - ACTA NEUROPATHOL
JF - ACTA NEUROPATHOL
SN - 0001-6322
IS - 2
ER -