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Meningioma DNA methylation grouping reveals biologic drivers and therapeutic vulnerabilities (array)

ABSTRACT: We report DNA methylation profiling on 565 meningiomas integrated with genetic, transcriptomic, biochemical, proteomic, and single-cell approaches to show meningiomas are comprised of 3 groups with distinct clinical outcomes, biological drivers, and therapeutic vulnerabilities. Merlin-intact meningiomas have the best outcomes and are distinguished by NF2/Merlin regulation of glucocorticoid signaling, apoptosis, and susceptibility to cytotoxic therapy. Immune-enriched meningiomas have intermediate outcomes and are distinguished by immune infiltration, HLA expression, and lymphatic vessels. Hypermitotic meningiomas have the worst outcomes and are distinguished by convergent genetic and epigenetic mechanisms driving the cell cycle and resistance to cytotoxic therapy. Our results establish a framework for understanding meningioma biology, and provide a foundation for new meningioma treatments.

ORGANISM(S): Homo sapiens

PROVIDER: GSE183647 | GEO | 2022/01/10

REPOSITORIES: GEO

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Project description:The majority of meningiomas are benign tumors associated with favorable outcomes; however, the less common aggressive variants with unfavorable outcomes often recur and may be due to sub-populations of less-differentiated cells residing within the tumor. These sub-populations of tumor cells, termed tumor-initiating cells, may be isolated from heterogeneous tumors when sorted or cultured in defined medium designed for enrichment of the tumor-initiating cells. We report the isolation and characterization of a population of tumor-initiating cells derived from an atypical meningioma. These meningioma-initiating cells (MICs) self-renew, differentiate, and can recapitulate the histological characteristics of the parental tumor when transplanted into athymic nude mice. Immunohistochemistry reveals protein expression patterns similar to neural stem and progenitor cells while genomic profiling verified the isolation of cancer cells (with defined meningioma chromosomal aberrations) from the bulk tumor. Furthermore, microarray analysis of gene expression reveals that many epithelial to mesenchymal transition genes are upregulated in the MICs, consistent with the presence of both neural stem cell and mature neural cell molecular markers seen in the derived cultures. Pathway analysis identifies biochemical processes and gene networks related to aberrant cell cycle progression, particularly the loss of heterozygosity of tumor suppressor genes CDKN2A (p16INK4A), p14ARF, and CDKN2B (p15INK4B). Flow cytometric analysis revealed the expression of CD44 and activated leukocyte adhesion molecule (ALCAM/CD166); these may prove to be markers able to identify this cell type. In conclusion, we identify a tumor-initiating population from an atypical meningioma that displays a unique phenotype and these results provide increased understanding of atypical meningioma progression. Part 1 of 2: Affymetrix SNP arrays were performed according to the manufacturer's directions on DNA extracted from primary tissue and their counterpart cell lines Part 2 of 2: Illumina gene expression array analysis was performed according to the manufacturer's directions on RNA extracted from cultured primary Meningioma and neural stem cell lines