Aggressive meningiomas appear to share a specific molecular signature: heightened activity of the EZH2 and E2F1 genes occurring together with alterations in the NF2 gene. That is the central conclusion of a study published in Acta Neuropathologica Communications, which combined gene-expression profiling of a meningioma discovery cohort, OncoPrint analyses of a previously published dataset, and laboratory testing of an EZH2 inhibitor in meningioma cell lines.
While mutations in a handful of genes such as CDKN2A and TERT are known to mark aggressive disease, the study’s authors note that coding alterations do not significantly contribute to meningioma aggressiveness beyond these rare exceptions. This gap motivated the research team, which included Ryota Sasao and Hikaru Sasaki among its authors, to investigate specific molecular pathways as potential therapeutic targets.
The investigators assembled a discovery cohort of 35 meningiomas, 26 of which were high-grade tumors. They analyzed these samples for genetic alterations and gene expression profiles. A subset of 28 tumors was then subjected to unsupervised hierarchical clustering, gene set enrichment analysis (GSEA), and gene set variation analysis (GSVA), computational methods that group tumors by expression patterns and identify which biological pathways are activated or silenced in each group.
The 28 tumors sorted cleanly into three clusters, which the researchers labeled Cluster M Low, Mid, and High. These clusters correlated with overall survival and WHO grade.
GSEA comparisons across the clusters revealed a two-step molecular trajectory. GSEA comparing the Cluster M subgroups showed that, moving from Low to Mid, meningioma aggressiveness increased via the downregulation of immune response-related gene sets. Moving from Mid to High, aggressiveness increased via the upregulation of cell proliferation-related gene sets. These findings were supported by GSVA using Hallmark gene sets and by hierarchical clustering based on copy number losses, with enrichment of the E2F target and MYC target gene sets in the high-grade clusters.
To confirm these patterns on a larger scale, the team performed OncoPrint analyses using a previously published dataset of meningiomas. The results showed that the most aggressive type of meningioma is characterized by the upregulation of EZH2 as well as E2F1, but notably not MYC, in combination with NF2 alterations. The OncoPrint analyses demonstrated that the most aggressive type of meningiomas is characterized by the upregulation of EZH2 as well as E2F1, but not MYC, in combination with NF2 alterations.
The study reports that meningiomas harboring NF2 alterations exhibit distinct biological behaviors depending on the expression of EZH2 and E2F1.
The researchers tested this idea directly in the laboratory. They evaluated an EZH2 inhibitor across multiple meningioma cell lines and found that meningioma cell growth was suppressed by the drug. This laboratory finding is a preclinical result in cell lines and does not yet establish clinical benefit in patients.
The study concludes that meningiomas harboring NF2 alterations exhibit distinct biological behaviors depending on the expression of EZH2 and E2F1, and that aggressive meningiomas are characterized by the upregulation of these pathways in combination with NF2 alterations. EZH2, the authors write, is a promising therapeutic target for high-grade meningiomas. Because the work relies on a discovery cohort of 35 tumors, a validation dataset, and cell-line experiments rather than clinical trials, translating these findings into treatments will require further study.
Subject of Research: Molecular pathways underlying aggressive meningiomas and EZH2 as a therapeutic target
Article Title: Upregulation of EZH2 and E2F1 in combination with NF2 alterations underlies the molecular characteristics of aggressive meningiomas
Article References: Sasao, R., Takimoto, T., Nakamura, K., Yokogami, K., Yamashita, S., Aimono, E., Ohba, S., Nishihara, H., Saya, H., & Sasaki, H. (2026). Upregulation of EZH2 and E2F1 in combination with NF2 alterations underlies the molecular characteristics of aggressive meningiomas. Acta Neuropathologica Communications. https://doi.org/10.1186/s40478-026-02470-0
Image Credits: AI Generated
DOI: 10.1186/s40478-026-02470-0
Keywords: meningioma, EZH2, E2F1, NF2, epigenetics, gene expression, brain tumor, EZH2 inhibitor, WHO grade, cell proliferation, Upregulation, combination
News Source: Juliet Wilcox. (November 5, 2026). EZH2 and E2F1 Upregulation with NF2 Alterations Drives Aggressive Meningiomas. Scienmag.
