Subject(s)
Meningeal Neoplasms , Meningioma , Mutation , Proto-Oncogene Proteins c-akt , Tumor Necrosis Factor Receptor-Associated Peptides and Proteins , Humans , Meningioma/genetics , Meningioma/pathology , Meningeal Neoplasms/genetics , Meningeal Neoplasms/pathology , Female , Proto-Oncogene Proteins c-akt/genetics , Middle Aged , Male , Tumor Necrosis Factor Receptor-Associated Peptides and Proteins/genetics , Foramen Magnum/pathology , Adult , AgedSubject(s)
Chromosomes, Human, Pair 1 , Meningeal Neoplasms , Meningioma , Neoplasm Recurrence, Local , Humans , Meningioma/genetics , Meningioma/pathology , Chromosomes, Human, Pair 1/genetics , Meningeal Neoplasms/genetics , Meningeal Neoplasms/pathology , Neoplasm Recurrence, Local/genetics , Neoplasm Recurrence, Local/pathology , Female , Male , Middle Aged , Aged , Chromosome Deletion , AdultABSTRACT
Meningiomas are the most common primary intracranial tumors and account for nearly 30% of all nervous system tumors. Approximately half of meningioma patients exhibit neurofibromin 2 (NF2) gene inactivation. Here, NF2 was shown to interact with the endoplasmic reticulum (ER) calcium (Ca2+) channel inositol 1,4,5-trisphosphate receptor 1 (IP3R1) in IOMM-Lee, a high-grade malignant meningioma cell line, and the F1 subdomain of NF2 plays a critical role in this interaction. Functional assays indicated that NF2 promotes the phosphorylation of IP3R (Ser 1756) and IP3R-mediated endoplasmic reticulum (ER) Ca2+ release by binding to IP3R1, which results in Ca2+-dependent apoptosis. Knockout of NF2 decreased Ca2+ release and promoted resistance to apoptosis, which was rescued by wild-type NF2 overexpression but not by F1 subdomain deletion truncation overexpression. The effects of NF2 defects on the development of tumors were further studied in mouse models. The decreased expression level of NF2 caused by NF2 gene knockout or mutation affects the activity of the IP3R channel, which reduces Ca2+-dependent apoptosis, thereby promoting the development of tumors. We elucidated the interaction patterns of NF2 and IP3R1, revealed the molecular mechanism through which NF2 regulates IP3R1-mediated Ca2+ release, and elucidated the new pathogenic mechanism of meningioma-related NF2 variants. Our study broadens the current understanding of the biological function of NF2 and provides ideas for drug screening of NF2-associated meningioma.
Subject(s)
Apoptosis , Calcium Signaling , Calcium , Inositol 1,4,5-Trisphosphate Receptors , Meningeal Neoplasms , Meningioma , Animals , Humans , Mice , Calcium/metabolism , Cell Line, Tumor , Endoplasmic Reticulum/metabolism , Inositol 1,4,5-Trisphosphate Receptors/metabolism , Inositol 1,4,5-Trisphosphate Receptors/genetics , Meningeal Neoplasms/metabolism , Meningeal Neoplasms/pathology , Meningeal Neoplasms/genetics , Meningioma/metabolism , Meningioma/pathology , Meningioma/genetics , Neurofibromin 2ABSTRACT
OBJECTIVES: The standard treatment for canine and feline meningiomas includes radiotherapy, surgical excision or combined therapy. However, new therapeutic approaches are required due to the possible recurrence or progression of meningiomas despite initial therapy. Adjunctive therapy with synthetic long-acting somatostatin (SST) analogues has been described in humans with SST-expressing tumours. The expression of SST receptors (SSTRs) by feline meningiomas is currently unknown, and there are little data about canine meningiomas. We hypothesized that SSTR is expressed by canine and feline meningiomas (S1). METHODS: Seven canines and 11 felines with histologically confirmed meningiomas underwent STTR screening. RNA expressions of SSTR1, SSTR2, SSTR3 and SSTR5 (canine) and SSTR1-SSTR 5 (feline) in fresh frozen and formalin-fixed and paraffin-embedded (FFPE) samples were investigated using real-time (RT)-qPCR. The expression of SSTR1 and SSTR2 in FFPE samples was evaluated using immunohistochemistry (IHC). The specificity of applied antibodies for canine and feline species was confirmed by western blotting. RESULTS: In canine meningiomas (n = 7), RNA expression of SSTR1, SSTR2 and SSTR5 was detected in all samples; SSTR3 RNA expression was detected in only 33% of samples. In feline meningiomas (n = 12), RNA expression of SSTR1, SSTR4, SSTR5 and SSTR2 was detected in 91%, 46%, 46% and 36% of samples, respectively; SSTR3 was not expressed. Overall, the detection rate was lower in FFPE samples. IHC revealed the expression of SSTR1 and SSTR2 in all samples from both species. However, it is important to exercise caution when interpreting IHC results due to the presence of diffuse background staining. CONCLUSIONS: SSTRs are widely expressed in canine and feline meningiomas, thereby encouraging further studies investigating SSTR expression to conduct trials about the effect of adjunctive therapy with long-acting SST-analogues.
Subject(s)
Cat Diseases , Dog Diseases , Meningioma , Receptors, Somatostatin , Receptors, Somatostatin/metabolism , Receptors, Somatostatin/genetics , Animals , Dogs , Cats , Cat Diseases/metabolism , Cat Diseases/genetics , Meningioma/veterinary , Meningioma/metabolism , Meningioma/genetics , Dog Diseases/metabolism , Dog Diseases/genetics , Meningeal Neoplasms/veterinary , Meningeal Neoplasms/metabolism , Meningeal Neoplasms/genetics , Female , MaleABSTRACT
Meningiomas, renowned for their histological diversity, are one of the most prevalent brain tumors. Some meningiomas show unusual histomorphology, especially in intraoperative rapid diagnosis. Therefore, clinical and radiological information is crucial for pathological diagnosis. Before the 2021 World Health Organization Classification of Tumors of the Central Nervous System(5th edition), pathological diagnosis relied solely on histopathological features. However, this classification introduced new diagnostic criteria for anaplastic meningiomas, which now include TERT promoter mutations and the homozygous deletion of CDKN2A/B, indicating the necessity of genetic analysis. Some rhabdoid and papillary meningiomas have BAP1 alterations, which tend to demonstrate an aggressive clinical course and may represent a phenotype of BAP1-related tumor predisposition syndrome. Heterozygous deletion of CDKN2A/B and loss of H3 p.K28me3(K27me3)are also associated with poor prognosis. Although some immunohistochemical markers like MTAP may serve as surrogates for the homozygous deletion of CKKN2A/B, genetic analysis is required to confirm TERT promoter mutations. Therefore, in routine clinical practice, neurosurgeons and pathologists prioritize appropriate formalin fixation to facilitate genetic analysis using pathological specimens.
Subject(s)
Meningeal Neoplasms , Meningioma , Meningioma/genetics , Meningioma/diagnosis , Meningioma/pathology , Humans , Meningeal Neoplasms/genetics , Meningeal Neoplasms/pathology , Meningeal Neoplasms/diagnosis , MutationABSTRACT
Biological molecular studies of meningiomas have also developed with the development of molecular biological methods. In 2013, Clark et al. reported that driver genetic mutations other than NF2, including TRAF7, KLF4, AKT1, and SMO, were associated with meningioma development. In 2017, Sahm et al. proposed a classification of meningiomas based on global methylation status, which was more accurate in predicting prognosis than conventional WHO grading. In 2022, based on this classification, various groups reported an integrated classification that comprehensively included some biological molecular abnormalities, such as DNA mutations, copy number alterations, and RNA sequences. This field is expected to elucidate the mechanism of meningioma development and further research is expected to lead to the development of effective molecularly targeted therapeutics and biomarkers of radiosensitivity in the future. In this article, we summarize the current status and prospects of these biological molecular studies.
Subject(s)
Kruppel-Like Factor 4 , Meningeal Neoplasms , Meningioma , Mutation , Humans , Meningioma/genetics , Prognosis , Meningeal Neoplasms/genetics , DNA MethylationABSTRACT
PURPOSE: Although meningiomas are the most common primary intracranial tumors, their genetic etiologies have not been fully elucidated. To date, only two genome-wide association studies (GWASs) have focused on European ancestries, despite ethnic differences in the incidence of meningiomas. The aim of this study was to conduct the first GWAS of Japanese patients with meningiomas to identify the SNPs associated with meningioma susceptibility. METHODS: In this multicenter prospective case-control study, we studied 401 Japanese patients with meningioma admitted in five institutions in Japan, and 50,876 control participants of Japanese ancestry enrolled in Biobank Japan. RESULTS: The quality control process yielded 536,319 variants and imputation resulted in 8,224,735 variants on the autosomes and 224,820 variants on the X chromosomes. This GWAS eventually revealed no genetic variants with genome-wide significance (P < 5 × 10 - 8) and observed no significant association in the previously reported risk variants rs11012732 and rs2686876 due to low minor allele frequency in the Japanese population. CONCLUSION: This is the first GWAS of meningiomas in East Asian populations and is expected to contribute to the development of GWAS research for meningiomas.
Subject(s)
Genetic Predisposition to Disease , Genome-Wide Association Study , Meningeal Neoplasms , Meningioma , Polymorphism, Single Nucleotide , Humans , Meningioma/genetics , Meningioma/epidemiology , Prospective Studies , Meningeal Neoplasms/genetics , Meningeal Neoplasms/epidemiology , Male , Female , Japan/epidemiology , Case-Control Studies , Middle Aged , Aged , AdultABSTRACT
BACKGROUND: Diagnosis and monitoring of leptomeningeal malignancy remain challenging, and are usually based on neurological, radiological, cerebrospinal fluid (CSF) and pathological findings. This study aimed to investigate the diagnostic performance of CSF metagenomic next-generation sequencing (mNGS) and chromosome copy number variations (CNVs) analysis in the detection of leptomeningeal malignancy. METHODS: Of the 51 patients included in the study, 34 patients were diagnosed with leptomeningeal malignancies, and 17 patients were diagnosed with central nervous system (CNS) inflammatory diseases. The Sayk's spontaneous cell sedimentation technique was employed for CSF cytology. And a well-designed approach utilizing the CSF mNGS-CNVs technique was explored for early diagnosis of leptomeningeal malignancy. RESULTS: In the tumor group, 28 patients were positive for CSF cytology, and 24 patients were positive for CSF mNGS-CNVs. Sensitivity and specificity of CSF cytology were 82.35% (95% CI: 66.83-92.61%) and 94.12% (95% CI: 69.24-99.69%). In comparison, sensitivity and specificity of CSF mNGS-CNV were 70.59% (95% CI: 52.33-84.29%) and 100% (95% CI: 77.08-100%). There was no significant difference in diagnostic consistency between CSF cytology and mNGS-CNVs (p = 0.18, kappa = 0.650). CONCLUSIONS: CSF mNGS-CNVs tend to have higher specificity compared with traditional cytology and can be used as a complementary diagnostic method for patients with leptomeningeal malignancies.
Subject(s)
DNA Copy Number Variations , High-Throughput Nucleotide Sequencing , Meningeal Neoplasms , Metagenomics , Humans , Male , Female , Meningeal Neoplasms/cerebrospinal fluid , Meningeal Neoplasms/genetics , Meningeal Neoplasms/diagnosis , High-Throughput Nucleotide Sequencing/methods , Middle Aged , DNA Copy Number Variations/genetics , Adult , Metagenomics/methods , Aged , Young Adult , Sensitivity and Specificity , Adolescent , CytologyABSTRACT
PURPOSE: The treatment of leptomeningeal metastasis (LM), a serious complication of advanced non-small cell lung cancer (NSCLC), presents challenges, particularly in patients with EGFR exon 20 insertion (ex20ins) mutations. METHODS: This study retrospectively analyzed data from 10 EGFR ex20ins-mutated NSCLC patients with LM admitted at our institution from May 2011 to June 2023. Circulating tumor DNA (ctDNA) from cerebrospinal fluid (CSF) and matched plasma samples was analyzed using next-generation sequencing. All patients received high-dose furmonertinib combined with intraventricular chemotherapy (IVC) as salvage therapy. Data on patient demographics, treatment efficacy, and safety outcomes were collected. RESULTS: The most common insertion mutation identified in this study was p.A767_V769dup (n = 4, 40%), followed by D770-N771insY (n = 2, 20%). Nine patients had EGFR ex20ins occurring in the EGFR loop region following the C-helix, whereas only one patient had an EGFR ex20ins (A763_Y764insFQEA) occurring in the C-helix of the tyrosine kinase domain. LM response assessment using the RANO-LM criteria revealed that 6 patients (60%, 95% CI 26.2-87.8%) achieved a response, 3 had stable disease, and 1 had progressive disease. The median progression-free survival and overall survival were estimated to be 6.5 months and 8.8 months, respectively. The most commonly reported treatment-related adverse events were rash (n = 7) and diarrhea (n = 7), with no treatment-related deaths occurring. CONCLUSIONS: The current study demonstrated that high-dose furmonertinib plus IVC as salvage treatment for patients with LM harboring EGFR ex20ins mutations had promising clinical benefits and a manageable safety profile.
Subject(s)
Carcinoma, Non-Small-Cell Lung , ErbB Receptors , Lung Neoplasms , Salvage Therapy , Humans , Male , Female , Middle Aged , ErbB Receptors/genetics , Lung Neoplasms/drug therapy , Lung Neoplasms/pathology , Lung Neoplasms/genetics , Aged , Retrospective Studies , Carcinoma, Non-Small-Cell Lung/drug therapy , Carcinoma, Non-Small-Cell Lung/pathology , Carcinoma, Non-Small-Cell Lung/genetics , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Exons , Adult , Mutation , Meningeal Neoplasms/drug therapy , Meningeal Neoplasms/secondary , Meningeal Neoplasms/genetics , Meningeal Carcinomatosis/drug therapy , Meningeal Carcinomatosis/secondary , Meningeal Carcinomatosis/genetics , Follow-Up Studies , Prognosis , Mutagenesis, InsertionalABSTRACT
Leptomeningeal disease (LMD) remains a rapidly lethal complication for late-stage melanoma patients. Here, we characterize the tumor microenvironment of LMD and patient-matched extra-cranial metastases using spatial transcriptomics in a small number of clinical specimens (nine tissues from two patients) with extensive in vitro and in vivo validation. The spatial landscape of melanoma LMD is characterized by a lack of immune infiltration and instead exhibits a higher level of stromal involvement. The tumor-stroma interactions at the leptomeninges activate tumor-promoting signaling, mediated through upregulation of SERPINA3. The meningeal stroma is required for melanoma cells to survive in the cerebrospinal fluid (CSF) and promotes MAPK inhibitor resistance. Knocking down SERPINA3 or inhibiting the downstream IGR1R/PI3K/AKT axis results in tumor cell death and re-sensitization to MAPK-targeting therapy. Our data provide a spatial atlas of melanoma LMD, identify the tumor-promoting role of meningeal stroma, and demonstrate a mechanism for overcoming microenvironment-mediated drug resistance in LMD.
Subject(s)
Melanoma , Meningeal Neoplasms , Stromal Cells , Tumor Microenvironment , Melanoma/genetics , Melanoma/pathology , Humans , Tumor Microenvironment/genetics , Meningeal Neoplasms/genetics , Meningeal Neoplasms/pathology , Stromal Cells/metabolism , Stromal Cells/pathology , Animals , Cell Line, Tumor , Mice , Gene Expression Regulation, Neoplastic , Transcriptome/genetics , Gene Expression Profiling , Meninges/pathology , Meninges/metabolism , Drug Resistance, Neoplasm/genetics , Signal Transduction , FemaleABSTRACT
Leptomeningeal metastasis (LM) is a lethal complication of malignant tumors, with an incidence rate of 3%-5% among patients with non-small cell lung cancer (NSCLC). LM poses significant challenges in diagnosis, has poor prognosis, limited treatment options, and lacks standardized criteria for evaluating therapeutic efficacy, making it a difficult aspect of NSCLC management. Circulating tumor DNA (ctDNA), shed from tumor cells and carrying cancer-related information, holds significant value in precision oncology. Cerebrospinal fluid (CSF), present in the subarachnoid space of the brain, the spinal cord, and the central canal, and in direct contact with meningeal tissues, serves as the fluid medium that best reflects the genetic characteristics of LM. In recent years, CSF ctDNA has become a focal point due to its multi-omics features, playing a crucial role in the management of central nervous system (CNS) metastatic tumors. Its applications span the entire continuum of care, including aiding in diagnosis, assessing treatment response, predicting prognosis, and analyzing resistance mechanisms. This article provides a concise overview of CSF ctDNA detection techniques and their clinical applications in patients with NSCLC-LM.â©.
Subject(s)
Carcinoma, Non-Small-Cell Lung , Circulating Tumor DNA , Lung Neoplasms , Meningeal Neoplasms , Humans , Carcinoma, Non-Small-Cell Lung/cerebrospinal fluid , Carcinoma, Non-Small-Cell Lung/genetics , Carcinoma, Non-Small-Cell Lung/pathology , Circulating Tumor DNA/cerebrospinal fluid , Circulating Tumor DNA/genetics , Circulating Tumor DNA/blood , Lung Neoplasms/pathology , Lung Neoplasms/cerebrospinal fluid , Lung Neoplasms/genetics , Meningeal Neoplasms/secondary , Meningeal Neoplasms/cerebrospinal fluid , Meningeal Neoplasms/geneticsABSTRACT
PURPOSE: Leptomeningeal metastases (LMs) exhibit a high incidence in patients with epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer (NSCLC) post-treatment with first- or second-generation EGFR tyrosine kinase inhibitors (TKIs). This investigation evaluates the efficacy, safety, and pharmacokinetics of 80 mg once daily osimertinib in patients with LMs resistant to prior first- or second-generation EGFR TKIs. MATERIALS AND METHODS: In this phase II multicenter, open-label, single-arm study, 80 mg osimertinib was administered to patients with EGFR-mutated NSCLC who had developed LMs subsequent to treatment with prior EGFR TKIs. The primary end point was overall survival (OS), assessed alongside objective response rate by the blinded independent central review (BICR) and a pharmacokinetic analysis of plasma and cerebrospinal fluid (CSF) on the first day of cycles 3 and 6. RESULTS: A total of 73 patients diagnosed with LM were treated with osimertinib, including 64 patients evaluable for the LM efficacy set-T790M negative (n = 62) and T790M positive (n = 2). The median OS in the full-analysis set was 15.6 months (95% CI, 11.5 to 20.2). The objective response rate for LM was 51.6%, including a 15.6% complete response, and the disease control rate was 81.3% by BICR in the LM efficacy evaluable set. The median LM progression-free survival by BICR was 11.2 months (95% CI, 7.7 to 15.3), the duration of response was 12.6 months (95% CI, 7.6 to 17.7), and OS was 15.0 months (95% CI, 11.3 to 18.7). Pharmacokinetic analysis showed that the CSF to free plasma osimertinib ratio was 22%. Most safety profiles were grade 1 and 2. CONCLUSION: The study demonstrates significant intracranial efficacy and survival benefits of 80 mg once daily osimertinib in NSCLC patients with LMs. The data support considering daily 80 mg of osimertinib as a treatment option for EGFR-mutated NSCLC patients with LMs, irrespective of T790M mutation status.
Subject(s)
Acrylamides , Aniline Compounds , Carcinoma, Non-Small-Cell Lung , ErbB Receptors , Lung Neoplasms , Mutation , Humans , Acrylamides/therapeutic use , Acrylamides/pharmacokinetics , Acrylamides/administration & dosage , Carcinoma, Non-Small-Cell Lung/drug therapy , Carcinoma, Non-Small-Cell Lung/genetics , Aniline Compounds/pharmacokinetics , Aniline Compounds/therapeutic use , Aniline Compounds/administration & dosage , Aniline Compounds/adverse effects , Male , Lung Neoplasms/drug therapy , Lung Neoplasms/genetics , Lung Neoplasms/pathology , Female , Middle Aged , ErbB Receptors/genetics , ErbB Receptors/antagonists & inhibitors , Aged , Adult , Aged, 80 and over , Antineoplastic Agents/pharmacokinetics , Antineoplastic Agents/therapeutic use , Antineoplastic Agents/administration & dosage , Antineoplastic Agents/adverse effects , Protein Kinase Inhibitors/pharmacokinetics , Protein Kinase Inhibitors/therapeutic use , Protein Kinase Inhibitors/administration & dosage , Protein Kinase Inhibitors/adverse effects , Meningeal Carcinomatosis/secondary , Meningeal Carcinomatosis/drug therapy , Meningeal Carcinomatosis/genetics , Meningeal Neoplasms/secondary , Meningeal Neoplasms/drug therapy , Meningeal Neoplasms/genetics , Indoles , PyrimidinesABSTRACT
BACKGROUND: External radiation therapy (RT) is often a primary treatment for inoperable meningiomas in the absence of established chemotherapy. Histone deacetylase 6 (HDAC6) overexpression, commonly found in cancer, is acknowledged as a driver of cellular growth, and inhibiting HDACs holds promise in improving radiotherapeutic efficacy. Downregulation of HDAC6 facilitates the degradation of ß-catenin. This protein is a key element in the Wnt/ß-catenin signalling pathway, contributing to the progression of meningiomas. METHODS: In order to elucidate the associations and therapeutic potential of HDAC6 inhibitors (HDAC6i) in conjunction with RT, we administered Cay10603, HDAC6i, to both immortalised and patient-derived meningioma cells prior to RT in this study. FINDINGS: Our findings reveal an increase in HDAC6 expression following exposure to RT, which is effectively mitigated with pre-treated Cay10603. The combination of Cay10603 with RT resulted in a synergistic augmentation of cytotoxic effects, as demonstrated through a range of functional assays conducted in both 2D as well as 3D settings; the latter containing syngeneic tumour microenvironment (TME). Radiation-induced DNA damage was augmented by pre-treatment with Cay10603, concomitant with the inhibition of ß-catenin and minichromosome maintenance complex component 2 (MCM2) accumulation within the nucleus. This subsequently inhibited c-myc oncogene expression. INTERPRETATION: Our findings demonstrate the therapeutic potential of Cay10603 to improve the radiosensitisation and provide rationale for combining HDAC6i with RT for the treatment of meningioma. FUNDING: This work was funded by Brain Tumour Research Centre of Excellence award to C Oliver Hanemann.
Subject(s)
Histone Deacetylase 6 , Histone Deacetylase Inhibitors , Meningioma , Humans , Histone Deacetylase 6/antagonists & inhibitors , Histone Deacetylase 6/metabolism , Histone Deacetylase 6/genetics , Meningioma/radiotherapy , Meningioma/pathology , Meningioma/metabolism , Meningioma/genetics , Cell Line, Tumor , Histone Deacetylase Inhibitors/pharmacology , Histone Deacetylase Inhibitors/therapeutic use , beta Catenin/metabolism , beta Catenin/genetics , Meningeal Neoplasms/radiotherapy , Meningeal Neoplasms/pathology , Meningeal Neoplasms/metabolism , Meningeal Neoplasms/genetics , Wnt Signaling Pathway/drug effects , Cell Proliferation/drug effects , Tumor Microenvironment/radiation effects , Tumor Microenvironment/drug effects , DNA Damage/radiation effectsABSTRACT
Meningioma is a prevalent intracranial malignancy known for its aggressive growth. Circular RNAs (circRNAs) play a crucial role in the development of various cancers. However, their involvement in meningioma remains understudied. This study aimed to investigate the function and underlying mechanism of hsa_circ_0004872 in meningioma. The molecular expression of hsa_circ_0004872, PD-L1 and EIF4A3 was identified by RT-qPCR and/or western blot assays. Cell viability, migration, and invasion were assessed through CCK-8 and Transwell assays, respectively. Cytotoxicity was determined using an LDH assay, and cell apoptosis was monitored by flow cytometry. The RNA and protein interactions were assessed through RNA-protein immunoprecipitation (RIP) and RNA pull down analyses. Our findings revealed that hsa_circ_0004872 expression was significantly downregulated in both meningioma tissue samples and cells. Overexpression of hsa_circ_0004872 inhibited the proliferation, metastasis, and immune escape of meningioma cells, as well as enhanced the cytotoxicity of CD8+ T cells by suppressing PD-L1. Furthermore, hsa_circ_0004872 directly interacted with EIF4A3, leading to the degradation of PD-L1 mRNA. Finally, inhibiting EIF4A3 improved the proliferation, metastasis, and immune escape of meningioma cells, as well as the cytotoxicity of CD8+ T cells. Our study demonstrated that hsa_circ_0004872 mitigated the proliferation, metastasis,and immune escape of meningioma cells by targeting the EIF4A3/PD-L1 axis. These findings suggested that hsa_circ_0004872 and EIF4A3 might serve as promising biological markers and therapeutic targets for meningioma treatment.
Subject(s)
B7-H1 Antigen , Cell Proliferation , Eukaryotic Initiation Factor-4A , Meningeal Neoplasms , Meningioma , RNA, Circular , Meningioma/pathology , Meningioma/immunology , Meningioma/genetics , Meningioma/metabolism , Humans , B7-H1 Antigen/metabolism , B7-H1 Antigen/genetics , RNA, Circular/genetics , Meningeal Neoplasms/pathology , Meningeal Neoplasms/genetics , Meningeal Neoplasms/immunology , Meningeal Neoplasms/metabolism , Eukaryotic Initiation Factor-4A/genetics , Eukaryotic Initiation Factor-4A/metabolism , Cell Line, Tumor , Gene Expression Regulation, Neoplastic , Cell Movement , Tumor Escape , Apoptosis , DEAD-box RNA HelicasesABSTRACT
INTODUCTION: Diffuse leptomeningeal glioneuronal tumors (DLGNTs) pose a rare and challenging entity within pediatric central nervous system neoplasms. Despite their rarity, DLGNTs exhibit complex clinical presentations and unique molecular characteristics, necessitating a deeper understanding of their diagnostic and therapeutic nuances. METHODS: This review synthesizes contemporary literature on DLGNT, encompassing epidemiology, clinical manifestations, pathological features, treatment strategies, prognostic markers, and future research directions. To compile the existing body of knowledge on DLGNT, a comprehensive search of relevant databases was conducted. RESULTS: DLGNT primarily affects pediatric populations but can manifest across all age groups. Its diagnosis is confounded by nonspecific clinical presentations and overlapping radiological features with other CNS neoplasms. Magnetic resonance imaging (MRI) serves as a cornerstone for DLGNT diagnosis, revealing characteristic leptomeningeal enhancement and intraparenchymal involvement. Histologically, DLGNT presents with low to moderate cellularity and exhibits molecular alterations in the MAPK/ERK signalling pathway. Optimal management of DLGNT necessitates a multidisciplinary approach encompassing surgical resection, chemotherapy, radiotherapy, and emerging targeted therapies directed against specific genetic alterations. Prognostication remains challenging, with factors such as age at diagnosis, histological subtypes, and genetic alterations influencing disease progression and treatment response. Long-term survival data are limited, underscoring the need for collaborative research efforts. CONCLUSION: Advancements in molecular profiling, targeted therapies, and international collaborations hold promise for improving DLGNT outcomes. Harnessing the collective expertise of clinicians, researchers, and patient advocates, can advance the field of DLGNT research and optimize patient care paradigms.
Subject(s)
Meningeal Neoplasms , Humans , Meningeal Neoplasms/therapy , Meningeal Neoplasms/pathology , Meningeal Neoplasms/diagnostic imaging , Meningeal Neoplasms/genetics , ChildABSTRACT
Meningiomas, although mostly benign, can be recurrent and fatal. World Health Organization (WHO) grading of the tumor does not always identify high-risk meningioma, and better characterizations of their aggressive biology are needed. To approach this problem, we combined 13 bulk RNA sequencing (RNA-seq) datasets to create a dimension-reduced reference landscape of 1,298 meningiomas. The clinical and genomic metadata effectively correlated with landscape regions, which led to the identification of meningioma subtypes with specific biological signatures. The time to recurrence also correlated with the map location. Further, we developed an algorithm that maps new patients onto this landscape, where the nearest neighbors predict outcome. This study highlights the utility of combining bulk transcriptomic datasets to visualize the complexity of tumor populations. Further, we provide an interactive tool for understanding the disease and predicting patient outcomes. This resource is accessible via the online tool Oncoscape, where the scientific community can explore the meningioma landscape.
Subject(s)
Meningeal Neoplasms , Meningioma , Transcriptome , Meningioma/genetics , Meningioma/pathology , Humans , Meningeal Neoplasms/genetics , Meningeal Neoplasms/pathology , Male , Female , Middle Aged , Gene Expression Regulation, Neoplastic , Algorithms , Gene Expression Profiling/methodsABSTRACT
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.
Subject(s)
Brain Neoplasms , Calcinosis , Meningioma , Humans , Calcinosis/genetics , Calcinosis/pathology , Meningioma/genetics , Meningioma/pathology , Brain Neoplasms/genetics , Brain Neoplasms/pathology , Brain Neoplasms/metabolism , Female , Meningeal Neoplasms/genetics , Meningeal Neoplasms/pathology , Brain Diseases/genetics , Brain Diseases/pathology , Brain Diseases/metabolismABSTRACT
Intratumor heterogeneity underlies cancer evolution and treatment resistance, but targetable mechanisms driving intratumor heterogeneity are poorly understood. Meningiomas are the most common primary intracranial tumors and are resistant to all medical therapies, and high-grade meningiomas have significant intratumor heterogeneity. Here we use spatial approaches to identify genomic, biochemical and cellular mechanisms linking intratumor heterogeneity to the molecular, temporal and spatial evolution of high-grade meningiomas. We show that divergent intratumor gene and protein expression programs distinguish high-grade meningiomas that are otherwise grouped together by current classification systems. Analyses of matched pairs of primary and recurrent meningiomas reveal spatial expansion of subclonal copy number variants associated with treatment resistance. Multiplexed sequential immunofluorescence and deconvolution of meningioma spatial transcriptomes using cell types from single-cell RNA sequencing show decreased immune infiltration, decreased MAPK signaling, increased PI3K-AKT signaling and increased cell proliferation, which are associated with meningioma recurrence. To translate these findings to preclinical models, we use CRISPR interference and lineage tracing approaches to identify combination therapies that target intratumor heterogeneity in meningioma cell co-cultures.
Subject(s)
Genetic Heterogeneity , Meningeal Neoplasms , Meningioma , Meningioma/genetics , Meningioma/pathology , Humans , Meningeal Neoplasms/genetics , Meningeal Neoplasms/pathology , DNA Copy Number Variations , Gene Expression Regulation, Neoplastic , Genomics/methods , Single-Cell Analysis , Cell Proliferation/genetics , Neoplasm Recurrence, Local/genetics , Signal Transduction/genetics , Cell Line, Tumor , TranscriptomeABSTRACT
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.
Subject(s)
DNA Methylation , Meningeal Neoplasms , Meningioma , Humans , Meningioma/genetics , Meningioma/pathology , Meningioma/classification , Male , Female , Meningeal Neoplasms/genetics , Meningeal Neoplasms/pathology , Meningeal Neoplasms/classification , Middle Aged , Aged , Adult , Retrospective Studies , Neoplasm Grading , Aged, 80 and over , Telomerase/genetics , Neoplasm Recurrence, Local/pathology , Neoplasm Recurrence, Local/geneticsABSTRACT
Meningiomas are non-glial tumors that are the most common primary brain tumors in adults. Although meningioma can possibly be cured with surgical excision, variations in atypical/anaplastic meningioma have a high recurrence rate and a poor prognosis. As a result, it is critical to develop novel therapeutic options for high-grade meningiomas. This review highlights the current histology of meningiomas, prevalent genetic and molecular changes, and the most extensively researched signaling pathways and therapies in meningiomas. It also reviews current clinical studies and novel meningioma treatments, including immunotherapy, microRNAs, cancer stem cell methods, and targeted interventions within the glycolysis pathway. Through the examination of the complex landscape of meningioma biology and the highlighting of promising therapeutic pathways, this review opens the way for future research efforts aimed at improving patient outcomes in this prevalent intracranial tumor entity.