Mutational patterns and regulatory networks in epigenetic subgroups of meningioma

Nagarajan Paramasivam, Daniel Hübschmann, Umut H. Toprak, Naveed Ishaque, Marian Neidert, Daniel Schrimpf, Damian Stichel, David Reuss, Philipp Sievers, Annekathrin Reinhardt, Annika K. Wefers, David T.W. Jones, Zuguang Gu, Johannes Werner, Sebastian Uhrig, Hans Georg Wirsching, Matthias Schick, Melanie Bewerunge-Hudler, Katja Beck, Stephanie BrehmerSteffi Urbschat, Marcel Seiz-Rosenhagen, Daniel Hänggi, Christel Herold-Mende, Ralf Ketter, Roland Eils, Zvi Ram, Stefan M. Pfister, Wolfgang Wick, Michael Weller, Rachel Grossmann, Andreas von Deimling, Matthias Schlesner, Felix Sahm

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Pages (from-to)295-308
Number of pages14
JournalActa Neuropathologica
Volume138
Issue number2
DOIs
StatePublished - 1 Aug 2019

Keywords

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

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