Mutational patterns and regulatory networks in epigenetic subgroups of meningioma

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 -