Mutational patterns and regulatory networks in epigenetic subgroups of meningioma

Publication

Mutational patterns and regulatory networks in epigenetic subgroups of meningioma

Journal Paper/Review - May 8, 2019

Paramasivam Nagarajan, 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, Bewerunge-Hudler Melanie, Schick Matthias, Hübschmann Daniel, Toprak Umut H, Ishaque Naveed, Neidert Marian Christoph, 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, Sahm Felix

Citation

Paramasivam N, Beck K, Brehmer S, Urbschat S, Seiz-Rosenhagen M, Hänggi D, Herold-Mende C, Ketter R, Eils R, Ram Z, Pfister S, Wick W, Weller M, Grossmann R, von Deimling A, Schlesner M, Bewerunge-Hudler M, Schick M, Hübschmann D, Toprak U, Ishaque N, Neidert M, Schrimpf D, Stichel D, Reuss D, Sievers P, Reinhardt A, Wefers A, Jones D, Gu Z, Werner J, Uhrig S, Wirsching H, Sahm F. Mutational patterns and regulatory networks in epigenetic subgroups of meningioma. Acta Neuropathol 2019; 138:295-308.

Type

Journal Paper/Review (English)

Journal

Acta Neuropathol 2019; 138

Publication Date

May 8, 2019

Issn Electronic

1432-0533

Pages

295-308

Brief description/objective

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.