Clinical implications of DNA methylation-based integrated classification of histologically defined grade 2 meningiomas.

The combination of DNA methylation analysis with histopathological and genetic features allows for a more accurate risk stratification and classification of meningiomas. Nevertheless, the implications of this classification for patients with grade 2 meningiomas, a particularly heterogeneous tumor entity, are only partially understood. We correlate the outcomes of histopathologically confirmed grade 2 meningioma with an integrated molecular-morphologic risk stratification and determine its clinical implications. Grade 2 meningioma patients treated at our institution were re-classified using an integrated risk stratification involving DNA methylation array-based data, copy number assessment and TERT promoter mutation analyses. Grade 2 meningioma cases according to the WHO 2021 criteria treated between 2007 and 2021 (n = 100) were retrospectively analyzed. The median clinical and radiographic follow-up periods were 59.8 and 54.4 months. A total of 38 recurrences and 17 deaths were observed. The local control rates of the entire cohort after 2-, 4-, and 6-years were 84.3%, 68.5%, and 50.8%, with a median local control time of 77.2 months. The distribution of the integrated risk groups were as follows: 31 low, 54 intermediate, and 15 high risk cases. In the multivariable Cox regression analysis, integrated risk groups were significantly associated with the risk of local recurrence (hazard ratio (HR) intermediate: 9.91, HR high-risk: 7.29, p < 0.01). Gross total resections decreased the risk of local tumor progression (HR gross total resection: 0.19, p < 0.01). The comparison of 1p status and integrated risk groups (low vs. intermediate/high) revealed nearly identical local control rates within their respective subgroups. In summary, only around 50% of WHO 2021 grade 2 meningiomas have an intermediate risk profile. Integrated molecular risk stratification is crucial to guide the management of patients with grade 2 tumors and should be routinely applied to avoid over- and undertreatment, especially concerning the use of adjuvant radiotherapy.

Exploring the Biological Overlapping Between Brain Calcifications and Tumorgenesis.

This article discusses a rare case of coexistent meningiomas and Primary familial brain calcification (PFBC). PFBC is a neurodegenerative disease characterized by brain calcifications and a variety of neuropsychiatric symptoms and signs, with pathogenic variants in specific genes. The study explores the potential link between PFBC and meningiomas, highlighting shared features like intralesional calcifications and common genes such as MEA6. The article also revisits PFBC patients developing other brain tumors, particularly gliomas, emphasizing the intersection of oncogenes like PDGFB and PDGFRB in both calcifications and tumor progression. In recent investigations, attention has extended beyond brain tumors to breast cancer metastasis, unveiling a noteworthy connection. These findings suggest a broader connection between brain calcifications and tumors, encouraging a reevaluation of therapeutic approaches for PFBC.

Meningioma: current updates on genetics, classification, and mouse modeling.

Meningiomas, the most common primary brain tumors in adults, are often benign and curable by surgical resection. However, a subset is of higher grade, shows aggressive growth behavior as well as brain invasion, and often recurs even after several rounds of surgery. Increasing evidence suggests that tumor classification and grading primarily based on histopathology do not always accurately predict tumor aggressiveness and recurrence behavior. The underlying biology of aggressive treatment-resistant meningiomas and the impact of specific genetic aberrations present in these high-grade tumors is still only insufficiently understood. Therefore, an in-depth research into the biology of this tumor type is warranted. More recent studies based on large-scale molecular data such as whole exome/genome sequencing, DNA methylation sequencing, and RNA sequencing have provided new insights into the biology of meningiomas and have revealed new risk factors and prognostic subtypes. The most common genetic aberration in meningiomas is functional loss of NF2 and occurs in both low- and high-grade meningiomas, whereas NF2-wildtype meningiomas are enriched for recurrent mutations in TRAF7, KLF4, AKT1, PI3KCA, and SMO and are more frequently benign. Most meningioma mouse models are based on patient-derived xenografts and only recently have new genetically engineered mouse models of meningioma been developed that will aid in the systematic evaluation of specific mutations found in meningioma and their impact on tumor behavior. In this article, we review recent advances in the understanding of meningioma biology and classification and highlight the most common genetic mutations, as well as discuss new genetically engineered mouse models of meningioma.

Letter to editor: single-cell transcriptome analysis upon ECM-remodeling meningioma cells of published cases.

This letter offers a nuanced evaluation of the recent study on single-cell transcriptome analysis of ECM-remodeling meningioma cells. While acknowledging the positive aspects, such as enhanced understanding of tumor heterogeneity and identification of potential therapeutic targets, it also highlights potential limitations, including challenges in data interpretation and validation.The focus on ECM-remodeling may inadvertently overshadow other critical aspects of tumor biology, necessitating a more holistic approach. The abstract concludes by emphasizing the importance of considering the broader context of tumor heterogeneity and microenvironmental influences in future research endeavors to improve clinical outcomes for patients with meningioma and other malignancies.

Meningioma achieves malignancy and erastin-induced ferroptosis resistance through FOXM1-AURKA-NRF2 axis.

The oncogene Aurora kinase A (AURKA) has been implicated in various tumor, yet its role in meningioma remains unexplored. Recent studies have suggested a potential link between AURKA and ferroptosis, although the underlying mechanisms are unclear. This study presented evidence of AURKA upregulation in high grade meningioma and its ability to enhance malignant characteristics. We identified AURKA as a suppressor of erastin-induced ferroptosis in meningioma. Mechanistically, AURKA directly interacted with and phosphorylated kelch-like ECH-associated protein 1 (KEAP1), thereby activating nuclear factor erythroid 2 related factor 2 (NFE2L2/NRF2) and target genes transcription. Additionally, forkhead box protein M1 (FOXM1) facilitated the transcription of AURKA. Suppression of AURKA, in conjunction with erastin, yields significant enhancements in the prognosis of a murine model of meningioma. Our study elucidates an unidentified mechanism by which AURKA governs ferroptosis, and strongly suggests that the combination of AURKA inhibition and ferroptosis-inducing agents could potentially provide therapeutic benefits for meningioma treatment.

[Methylthioadenosine phosphorylase and p16 as surrogate diagnostic markers for CDKN2A homozygous deletion in brain tumors].

Objective: To examine whether immunohistochemistry of methylthioadenosine phosphorylase (MTAP) and p16 could be used to predict the CDKN2A status in various brain tumors. Methods: A total of 118 cases of IDH-mutant astrocytomas, 16 IDH-wildtype glioblastoma, 17 polymorphic xanthoastrocytoma (PXA) and 20 meningiomas diagnosed at Xuanwu Hospital, Capital Medical University, Beijing, China from November 2017 to October 2023 were collected and analyzed. The CDKN2A status was detected by using fluorescence in situ hybridization or next-generation sequencing. Expression of MTAP and p16 proteins was detected with immunohistochemistry. The association of loss of MTAP/p16 expression with CDKN2A homozygous/heterozygous deletion was examined. Results: Among the 118 cases of IDH-mutant astrocytoma, 13 cases showed homozygous deletion of CDKN2A. All of them had no expression of MTAP while 9 cases had no expression of p16. Among the 16 cases of IDH wild-type glioblastoma, 6 cases showed homozygous deletion of CDKN2A. All 6 cases had no expression of MTAP, while 3 of these cases had no expression of p16 expression. Among the 17 PXA cases, 4 cases showed homozygous deletion of CDKN2A, and the expression of MTAP and p16 was also absent in these 4 cases. Among the 20 cases of meningiomas, 4 cases showed homozygous deletion of CDKN2A. Their expression of MTAP and p16 was also absent. Among the four types of brain tumors, MTAP was significantly correlated with CDKN2A homozygous deletion (P<0.05), with a sensitivity of 100%. However, it was only significantly correlated with the loss of heterozygosity (LOH) of CDKN2A in astrocytomas (P<0.001). P16 was associated with CDKN2A homozygous deletion in IDH-mutant astrocytoma and PXA (P<0.001), but not with the LOH of CDKN2A. Its sensitivity and specificity were lower than that of MTAP. Conclusions: MTAP could serve as a predictive surrogate for CDKN2A homozygous deletion in adult IDH-mutant astrocytoma, PXA, adult IDH-wildtype glioblastoma and meningioma. However, p16 could only be used in the first two tumor types, and its specificity and sensitivity are lower than that of MTAP.

Hsa_circ_0004872 alleviates meningioma progression by sponging miR-190a-3p/PTEN signaling.

BACKGROUND: Meningioma, the most prevalent intracranial tumor, possesses a significant propensity for malignant transformation. Circular RNAs (circ-RNAs), a class of non-coding RNAs, have emerged as crucial players in tumorigenesis. This study explores the functional relevance of hsa_circ_0004872, a specific circ-RNA, in the context of meningioma. METHODS: Molecular structure and stability of hsa_circ_0004872 were elucidated through PCR identification. Meningioma cell proliferation and apoptosis were assessed using the CCK-8 assay and flow cytometry, respectively. Gene and protein expression were analyzed via qRT-PCR and western blot. Molecular interactions were confirmed through dual-luciferase reporter gene and RIP assays. RESULTS: Hsa_circ_0004872, derived from exons 2 to 4 of the host gene MAPK1, demonstrated enhanced stability compared to its host MAPK1. Clinical data described that hsa_circ_0004872 was reduced in meningioma tissues and cell lines, and negatively correlated to poor survival rate of meningioma patients. Overexpression of hsa_circ_0004872 exhibited inhibitory effects on cell proliferation and promotion of apoptosis in vitro. Subsequent investigations unveiled a direct interaction between hsa_circ_0004872 and miR-190a-3p, leading to the activation of the PI3K/AKT signaling pathway through targeting PTEN. Notably, miR-190a-3p silence accelerated the apoptosis and proliferation inhibition of meningioma cells by inactivating PTEN/PI3K/AKT signaling, while miR-190a-3p overexpression showed an opposite effect, which greatly reversed the anti-tumor effects of hsa_circ_0004872 overexpression. CONCLUSION: In summary, our findings highlighted the intricate role of hsa_circ_0004872 in meningioma, shedding light on the regulatory mechanisms involving circ-RNAs in tumor progression. This positions hsa_circ_0004872 as a potential key regulatory factor in meningioma with implications for future therapeutic interventions.

Inhibition of BMP signaling pathway induced senescence and calcification in anaplastic meningioma.

PURPOSE: Meningiomas are the most common type of brain tumors and are generally benign, but malignant atypical meningiomas and anaplastic meningiomas frequently recur with poor prognosis. The metabolism of meningiomas is little known, so few effective treatment options other than surgery and radiation are available, and the targets for treatment of recurrence are not well defined. The Aim of this paper is to find the therapeutic target. METHODS: The effects of bone morphogenetic protein (BMP) signal inhibitor (K02288) and upstream regulator Gremlin2 (GREM2) on meningioma's growth and senescence were examined. In brief, we examined as follows: 1) Proliferation assay by inhibiting BMP signaling. 2) Comprehensive analysis of forced expression GREM2.3) Correlation between GREM2 mRNA expression and proliferation marker in 87 of our clinical samples. 4) Enrichment analysis between GREM2 high/low expressed groups using RNA-seq data (42 cases) from the public database GREIN. 5) Changes in metabolites and senescence markers associated with BMP signal suppression. RESULTS: Inhibitors of BMP receptor (BMPR1A) and forced expression of GREM2 shifted tryptophan metabolism from kynurenine/quinolinic acid production to serotonin production in malignant meningiomas, reduced NAD + /NADH production, decreased gene cluster expression involved in oxidative phosphorylation, and caused decrease in ATP. Finally, malignant meningiomas underwent cellular senescence, decreased proliferation, and eventually formed psammoma bodies. Reanalyzed RNA-seq data of clinical samples obtained from GREIN showed that increased expression of GREM2 decreased the expression of genes involved in oxidative phosphorylation, similar to our experimental results. CONCLUSIONS: The GREM2-BMPR1A-tryptophan metabolic pathway in meningiomas is a potential new therapeutic target.

Single-cell transcriptome analysis upon ECM-remodeling meningioma cells.

Meningiomas are the most common tumours that primarily arise in the central nervous system, but their intratumoural heterogeneity has not yet been thoroughly studied. We aimed to investigate the transcriptome characteristics and biological properties of ECM-remodeling meningioma cells. Single-cell RNA sequencing (ScRNA-seq) data from meningioma samples were acquired and used for analyses. We conducted comprehensive bioinformatics analyses, including screening for differentially expressed genes (DEGs), Kyoto Encyclopedia of Genes and Genomes (KEGG) signaling pathway and Gene Ontology (GO) term enrichment analyses, Gene Set Enrichment Analysis (GSEA), protein-protein interaction (PPI) analysis, and copy number variation (CNV) analysis on single-cell sequencing data from meningiomas. Eighteen cell types, including six meningioma subtypes, were identified in the data. ECM-remodeling meningioma cells (MGCs) were mainly distributed in brain-tumour interface tissues. KEGG and GO enrichment analyses revealed that 908 DEGs were mainly related to cell adhesion, extracellular matrix organization, and ECM-receptor interaction. GSEA analysis demonstrated that homophilic cell adhesion via plasma membrane adhesion molecules was significantly enriched (NES = 2.375, P < 0.001). CNV analysis suggested that ECM-remodeling MGCs showed considerably lower average CNV scores. ECM-remodeling MGCs predominantly localized at the brain-tumour interface area and adhere stably to the basement membrane with a lower degree of malignancy. This study provides novel insights into the malignancy of meningiomas.

A gain of function mutation in AKT1 increases hexokinase 2 and diminishes oxidative stress in meningioma.

Increasing evidence suggests the oncogenic role of missense mutation (AKT1-E17K) of AKT1 gene in meningiomas. Upon investigating the connection between the pro-tumorigenic role of AKT1-E17K and cellular metabolic adaptations, elevated levels of glycolytic enzyme hexokinase 2 (HK2) was observed in meningioma patients with AKT1-E17K compared to patients harboring wild-type AKT1. In vitro experiments also suggested higher HK2 levels and its activity in AKT1-E17K cells. Treatment with the conventional drug of choice AZD5363 (a pan AKT inhibitor) enhanced cell death and diminished HK2 levels in AKT1 mutants. Given the role of AKT phosphorylation in eliciting inflammatory responses, we observed increased levels of inflammatory mediators (IL-1ß, IL6, IL8, and TLR4) in AKT1-E17K cells compared to AKT1-WT cells. Treatment with AKT or HK2 inhibitors dampened the heightened levels of inflammatory markers in AKT1-E17K cells. As AKT and HK2 regulates redox homeostasis, diminished ROS generation concomitant with increased levels of NF-E2- related factor 2 (Nrf2) and superoxide dismutase 1 (SOD1) were observed in AKT1-E17K cells. Increased sensitivity of AKT1-E17K cells to AZD5363 in the presence of HK2 inhibitor Lonidamine was reversed upon treatment with ROS inhibitor NAC. By affecting metabolism, inflammation, and redox homeostasis AKT1-E17K confers a survival advantage in meningioma cells. Our findings suggest that targeting AKT-HK2 cross-talk to induce ROS-dependent cell death could be exploited as novel therapeutic approach in meningiomas.

Characteristics of MicroRNA Expression Depending on the Presence or Absence of Meningioma in Patients with Neurofibromatosis Type 2: A Secondary Analysis.

Meningioma is the second most frequent tumor in patients with neurofibromatosis type 2 (NF2). The presence of meningioma is believed to be a negative prognostic marker in these patients. However, the molecular mechanisms involved in the tumorigenesis of NF2-associated meningioma are not well characterized. Epigenetic regulation, including microRNAs (miRNAs), may be involved in the development of different tumor types in patients with NF2. The objective of this study is to explore the different characteristics of serum miRNA expression depending on the presence or absence of meningioma in patients with NF2. Nine patients with NF2 who were treated at the Department of Neurosurgery, Hiroshima University Hospital, were included. Total RNA (including small RNAs) was extracted from serum samples for the preparation of a small RNA library for next-generation sequencing analysis. Differentially expressed miRNAs (DEMs) were analyzed using the DESeq2 package to compare the characteristic miRNA expression profiles of patients with and without meningioma. In small RNA sequencing analysis, out of a total of 1,879 miRNAs registered in the database, the expressions of 657 miRNAs were observed. In DEM analysis, the expressions of four miRNAs, namely, hsa-miR-664b, hsa-miR-7706, hsa-miR-590, and hsa-miR-6513, were downregulated in patients with NF2 with meningioma compared with patients with NF2 without meningioma. Hsa-miR-193a was identified as the only upregulated miRNA in patients with NF2 with meningioma. In conclusion, we identified different circulating miRNA expression characteristics depending on the presence or absence of meningioma in patients with NF2.

Coexistence of meningioma and craniofacial fibrous dysplasia: a case series of clinicopathological study and literature review.

BACKGROUND: The co-existence of meningioma and craniofacial fibrous dysplasia (CFD) is rare. Due to the similar radiological characteristics, it is challenging to differentiate such co-existence from solitary hyperostotic meningioma resulting in a dilemma of prompt diagnosis and appropriate intervention. METHOD: We conducted a retrospective review of the data from 21 patients with concomitant meningioma and CFD who were treated at Beijing Tiantan Hospital from 2003 to 2021. We summarized their clinicopathological features and performed a comprehensive literature review. Additionally, we tested the characteristic pathogenic variants in exon 8 and 9 of GNAS gene and the expression of corresponding α-subunit of the stimulatory G protein (Gαs) related to CFD to explore the potential interactions between these two diseases. RESULTS: The cohort comprised 4 men and 17 women (mean age, 45.14 years). CFD most commonly involved the sphenoid bone (n = 10) and meningiomas were predominantly located at the skull base (n = 12). Surgical treatment was performed in 4 CFD lesions and 14 meningiomas. Simpson grade I-II resection was achieved in 12 out of the 14 resected meningiomas and almost all of them were classified as WHO I grade (n = 13). The mean follow-up duration was 56.89 months and recurrence was noticed in 2 cases. Genetic study was conducted in 7 tumor specimens and immunohistochemistry was accomplished in 8 samples showing that though GNAS variant was not detected, Gαs protein were positively expressed in different degrees. CONCLUSIONS: We presented an uncommon case series of co-diagnosed meningioma and CFD and provided a detailed description of its clinicopathological features, treatment strategy and prognosis. Although a definite causative relationship had not been established, possible genetic or environmental interplay between these two diseases could not be excluded. It was challenging to initiate prompt diagnosis and appropriate treatment for concomitant meningioma and CFD because of its similar radiological manifestations to meningioma with reactive hyperostosis. Personalized and multi-disciplinary management strategies should be adopted for the co-existence of meningioma and CFD.

p16 Immunohistochemistry as a Screening Tool for Homozygous CDKN2A Deletions in CNS Tumors.

The 2021 World Health Organization classification of tumors of the central nervous system emphasizes the significance of molecular parameters for an integrated diagnosis. Homozygous deletion of cyclin-dependent kinase inhibitor 2a (CDKN2A) has been associated with an adverse prognosis in IDH -mutant gliomas, supratentorial ependymomas, meningiomas, and MPNST. In this study, we examined the value of p16 protein immunohistochemistry as a rapid and cost-effective screening tool for a homozygous CDKN2A deletion. Genetic analyses for CDKN2A in 30 pleomorphic xanthoastrocytomas, 32 IDH -wild-type high-grade gliomas, 40 supratentorial ependymomas with ZFTA-RELA gene fusion, 21 IDH-mutant astrocytomas, and 24 meningiomas were performed mainly by a molecular inversion probe assay, a high-resolution, quantitative technology for the assessment of chromosomal copy number alterations. Immunohistochemistry for p16 proved to have a high positive predictive value (range 90% to 100%) and an overall low negative predictive value (range 22% to 93%) for a homozygous CDKN2A deletion. In a setting where molecular testing is limited for cost and time reasons, p16 immunohistochemistry serves as a useful and rapid screening tool for identifying cases that should be subjected to further molecular testing for CDKN2A deletions.

Cases of Mixed Schwannoma-Meningioma With and Without Neurofibromatosis 2 with Emphasis on Tumorigenesis.

Concurrent occurrence of schwannoma and meningiomas are rare, and are found especially in association with neurofibromatosis type 2 (NF2). Occurrence of mixed tumor without the aforementioned conditions is extremely rare. We present three cases of mixed tumor in different locations, including two with NF2 and one without NF2. We analyse the relationship of mixed tumor with NF2 and its clinical implications. Presence of mixed schwannoma-meningioma should prompt screening for NF2. Thus aids in early diagnosis of unsuspected NF2 cases. We observed that irrespective of different locations, cases with NF2 showed frequent recurrence of schwannoma as compared to case who did not fit in the existing clinical criteria for NF2. Collision tumor and thereby NF2 mutations indicates the prognosis and recurrence of the tumor, thereby guides in deciding the management.

Atypical meningioma: Histopathological, genetic, and epigenetic features to predict recurrence risk.

Grading assessed according to World Health Organization (WHO) criteria is a major prognostic factor for determining the risk of recurrence in patients with meningiomas and establishing the most appropriate therapeutic strategy after surgery. However, the main issue is to predict the recurrence risk of WHO grade 2 meningioma and, more specifically, of the atypical subtype. Indeed, owing to a reported recurrence rate of 50%, either radiotherapy or observation is currently considered an option after gross total surgical resection of atypical meningiomas. These heterogeneous clinical outcomes are likely related to the broad histopathological diagnostic criteria for this subtype, and whether meningiomas only present as brain invasion should be classified as atypical remains controversial. Over the last few years, several studies have shown that DNA methylation profiling, next-generation sequencing, and transcriptomics can better stratify meningiomas for their recurrence risk than histology. The main limitations to the widespread use of these approaches to classify meningiomas are their high cost and the need for sophisticated technologies. However, all studies concurred that atypical meningiomas without chromosome 1p deletion display a low recurrence risk, suggesting that the assessment of this cytogenetic alteration could represent an easy and quick method to determine which patients could benefit from adjuvant treatment after surgery. In addition, prognostically unfavorable molecular groups can be distinguished using specific immunostainings, although further validation is required.

A novel BRAF::PTPRN2 fusion in meningioma: a case report.

Gene fusion events have been linked to oncogenesis in many cancers. However, gene fusions in meningioma are understudied compared to somatic mutations, chromosomal gains/losses, and epigenetic changes. Fusions involving B-raf proto-oncogene, serine/threonine kinase (BRAF) are subtypes of oncogenic BRAF genetic abnormalities that have been reported in certain cases of brain tumors, such as pilocytic astrocytomas. However, BRAF fusions have not been recognized in meningioma. We present the case of an adult female presenting with episodic partial seizures characterized by déjà vu, confusion, and cognitive changes. Brain imaging revealed a cavernous sinus and sphenoid wing mass and she underwent resection. Histopathology revealed a World Health Organization (WHO) grade 1 meningioma. Genetic profiling with next generation sequencing and microarray analysis revealed an in-frame BRAF::PTPRN2 fusion affecting the BRAF kinase domain as well as chromothripsis of chromosome 7q resulting in multiple segmental gains and losses including amplifications of cyclin dependent kinase 6 (CDK6), tyrosine protein-kinase Met (MET), and smoothened (SMO). Elevated pERK staining in tumor cells provided evidence of activated mitogen-activated protein kinase (MAPK) signaling. This report raises the possibility that gene fusion events may be involved in meningioma pathogenesis and warrant further investigation.