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Acta Neuropathol. 2019 Aug;138(2):295-308. doi: 10.1007/s00401-019-02008-w. Epub 2019 May 8.

Mutational patterns and regulatory networks in epigenetic subgroups of meningioma.

Author information

1
Division of Theoretical Bioinformatics, German Cancer Research Center (DKFZ), Heidelberg, Germany.
2
Heidelberg Center for Personalized Oncology (DKFZ-HIPO), German Cancer Research Center (DKFZ), Heidelberg, Germany.
3
Division of Stem Cells and Cancer, DKFZ, Heidelberg, Germany.
4
Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM gGmbH), Heidelberg, Germany.
5
Department of Pediatric Oncology, Hematology and Immunology, University Hospital, Heidelberg, Germany.
6
Division Neuroblastoma Genomics, German Cancer Research Center (DKFZ), Heidelberg, Germany.
7
Hopp-Children's Cancer Center at the NCT Heidelberg (KiTZ), Heidelberg, Germany.
8
Center for Digital Health, Berlin Institute of Health and Charité Universitätsmedizin Berlin, Berlin, Germany.
9
Department of Neurosurgery, University Hospital of Zürich, Zurich, Switzerland.
10
Department of Neuropathology, University Hospital Heidelberg, Im Neuenheimer Feld 224, 69120, Heidelberg, Germany.
11
Clinical Cooperation Unit Neuropathology, German Consortium for Translational Cancer Research (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany.
12
Pediatric Glioma Research Group, German Consortium for Translational Cancer Research (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany.
13
Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
14
German Cancer Consortium (DKTK), Heidelberg, Germany.
15
Department of Biological Oceanography, Leibniz Institute of Baltic Sea Research, Rostock, Germany.
16
Division of Applied Bioinformatics, German Cancer Research Center (DKFZ), Heidelberg, Germany.
17
Department of Neurology, University Hospital and University of Zurich, Zurich, Switzerland.
18
Genomics and Proteomics Core Facility, Microarray Unit, German Cancer Research Center (DKFZ), Heidelberg, Germany.
19
Department of Neurosurgery, University Hospital Mannheim, University of Heidelberg, Mannheim, Germany.
20
Department of Neurosurgery, University Hospital Homburg Saar, Homburg, Germany.
21
Division of Experimental Neurosurgery, Department of Neurosurgery, University Hospital Heidelberg, Heidelberg, Germany.
22
Health Data Science Unit, Bioquant, Medical Faculty, University of Heidelberg, Heidelberg, Germany.
23
Department of Neurosurgery, Tel Aviv Medical Center, Tel Aviv, Israel.
24
Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel.
25
Clinical Cooperation Unit Neurooncology, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany.
26
Department of Neurology and Neurooncology Program, National Center for Tumor Diseases, Heidelberg University Hospital, Heidelberg, Germany.
27
Bioinformatics and Omics Data Analytics, German Cancer Research Center (DKFZ), Heidelberg, Germany.
28
Hopp-Children's Cancer Center at the NCT Heidelberg (KiTZ), Heidelberg, Germany. felix.sahm@med.uni-heidelberg.de.
29
Department of Neuropathology, University Hospital Heidelberg, Im Neuenheimer Feld 224, 69120, Heidelberg, Germany. felix.sahm@med.uni-heidelberg.de.
30
Clinical Cooperation Unit Neuropathology, German Consortium for Translational Cancer Research (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany. felix.sahm@med.uni-heidelberg.de.

Abstract

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.

KEYWORDS:

DNA methylation; Meningioma; Molecular classification; Mutational signatures; NF2; Whole genome sequencing

PMID:
31069492
DOI:
10.1007/s00401-019-02008-w

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