Mutational patterns and regulatory networks in epigenetic subgroups of meningioma

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 subgroupspecific 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.

Comprehending Meningioma Signaling Cascades Using Multipronged Proteomics Approaches & Targeted Validation of Potential Markers

“…With the advent of genomics platforms, the implications of mutations in NF2 as well as Non-NF2 tumors harboring mutations at TRAF7, KLF4, and AKT1 have been recognized ( 3 ). Recent research has also highlighted novel insights into the methylation patterns and have proposed the existence of multiple subtypes of meningiomas based on their epigenetic signatures ( 4 ). However, not many proteomics studies have been employed for deciphering the perturbations at the protein level.…”

Occurrence of Fibrotic Tumor Vessels in Grade I Meningiomas Is Strongly Associated with Vessel Density, Expression of VEGF, PlGF, IGFBP-3 and Tumor Recurrence

“…In recent years new data concerning the molecular pathological background of meningiomas have been obtained. This not only facilitates the diagnosis of meningiomas but also offers the possibility to identify new prognostic and therapeutic targets [ 6 , 7 , 8 , 9 ].…”

Multiplatform genomic profiling and magnetic resonance imaging identify mechanisms underlying intratumor heterogeneity in meningioma

“…Meningioma is a genetic disease that is common in patients with neurofibromatosis type 2, a complex autosomal disorder caused by germline heterozygous loss of function mutations in the tumor suppressor NF2 7 . While NF2 mutations are also common in sporadic meningiomas 8,9 , clinically actionable somatic variants in meningiomas are rare and generally not associated with adverse outcomes [10][11][12][13][14][15][16][17][18][19] , with infrequent exceptions 20,21 . Classification of meningiomas based on DNA methylation predicts outcomes better than somatic variants or histologic grade 15,19,22,23 , but DNA methylation profiles have not elucidated biologic drivers or targets for molecular therapy to treat meningioma patients.…”