Genetic/molecular alterations of meningiomas and the signaling pathways targeted

This is an open-access article distributed under the terms of the Creative Commons Attribution License.-- et al.Meningiomas are usually considered to be benign central nervous system tumors; however, they show heterogenous clinical, histolopathological and cytogenetic features associated with a variable outcome. In recent years important advances have been achieved in the identification of the genetic/molecular alterations of meningiomas and the signaling pathways involved. Thus, monosomy 22, which is often associated with mutations of the NF2 gene, has emerged as the most frequent alteration of meningiomas; in addition, several other genes (e.g. AKT1, KLF4, TRAF7, SMO) and chromosomes have been found to be recurrently altered often in association with more complex karyotypes and involvement of multiple signaling pathways. Here we review the current knowledge about the most relevant genes involved and the signaling pathways targeted by such alterations. In addition, we summarize those proposals that have been made so far for classification and prognostic stratification of meningiomas based on their genetic/genomic features.This work was partially supported by grants from the Fundação para a Ciência e Tecnologia (PIC/IC/83108/2007, FCT, Portugal), Fondo de Investigaciones Sanitarias (RD12/0036/0048, Instituto de Salud Carlos III (ISCIII/FEDER), Ministerio de Sanidad y Consumo, Madrid, Spain), and Consejeria Sanidad Junta de Castilla y León, Gerencia Regional de Salud: GRS689/A/11, and Proyecto Intramural-IBSAL IB14-05. Patrícia Domingues is partially supported by a grant (SFRH/BD/64799/2009) from FCT. Maria Dolores Tabernero is supported by IECSCYL (Soria, Spain).Peer Reviewe

The correlation of clinical and chromosomal alterations of benign meningiomas and their recurrences

Meningiomas (MGs) are the frequent benign intracranial tumors. Their complete removal does not always guarantee relapse-free survival. Recurrence-associated chromosomal anomalies in MGs haves been proposed as prognostic factors in addition to the World Health Organisation (WHO) grading, tumor size and resection rate. The aim of this study was to evaluate the frequency of deletions on chromosomes in sporadic MGs and to correlate them with the clinical findings and tumor behaviour. Along with survival, the tumor recurrence was the main endpoint. Chromosomal loss of heterozygosity (LOH) was studied. 46 benign MGs were subjected to the analysis, complete tumor resection was intended and no early mortalities were observed. Incomplete removal was related to parasagittal location and psammomatous hisptopathology (p<0.01). Chromosomal alterations were present in 82.6% of cases; LOH at 22q (67.4%) and 1p (34.8%) were the most frequent and associated with male sex (p=0.04). Molecular findings were not specific for any of the histopathologic grade. Tumor recurrence (14 of 46) correlated with tumor size (≥35mm), LOH at 1p, 14q, coexistence of LOH at 1p/14q, 10q/14q, ‘complex karyotype’ status (≥2 LOHs excluding 22q), patient age (younger <35), and Simpson grading of resection rate (≥3 of worse prognosis). The last 3 variables were independent significant prognostic factors in multivariate analysis and of the same importance in recurrence prediction (Receiver Operating Characteristic curves comparison p>0.05). Among the cases of recurrence, tumor progression was observed in 3 of 14. In 2 cases, LOH on 1p and/or coexistence of LOH 1p/14q correlated with anaplastic transformation

Meningioma recurrence

Meningioma accounts for more than 30% of all intracranial tumours. It affects mainly the elderly above the age of 60, at a female:male ratio of 3:2. The prognosis is variable: it is usually favourable with no progression in tumour grade and no recurrence in WHO grade 1 tumours. However, a minority of tumours represent atypical (grade 2) or anaplastic (grade 3) meningiomas; this heterogeneity is also reflected in histopathological appearances. Irrespective of the grade, the size of the tumour and the localisation may have severe, sometimes lethal consequences. Following neurosurgical interventions to remove the tumour, recurrence and progression in WHO grade may occur. Our knowledge on predisposing histomorphological and molecular factors of recurrence is rather limited. These can be classified as I) demographic II) environmental, III) genetic and epigenetic IV) imaging, V) neuropathological, and VI) neurosurgical. In view of the complex background of tumour recurrence, the recognition of often subtle signs of increased risk of recurrence requires close collaboration of experts from several medical specialties. This multidisciplinary approach results in better therapy and fewer complications related to tumour recurrence

Circulating Tumor Biomarkers in Meningiomas Reveal a Signature of Equilibrium Between Tumor Growth and Immune Modulation

Meningiomas are primary central nervous system (CNS) tumors that originate from the arachnoid cells of the meninges. Recurrence occurs in higher grade meningiomas and a small subset of Grade I meningiomas with benign histology. Currently, there are no established circulating tumor markers which can be used for diagnostic and prognostic purposes in a non-invasive way for meningiomas. Here, we aimed to identify potential biomarkers of meningioma in patient sera. For this purpose, we collected preoperative (n = 30) serum samples from the meningioma patients classified as Grade I (n = 23), Grade II (n = 4), or Grade III (n = 3). We used a high-throughput, multiplex immunoassay cancer panel comprising of 92 cancer-related protein biomarkers to explore the serum protein profiles of meningioma patients. We detected 14 differentially expressed proteins in the sera of the Grade I meningioma patients in comparison to the age- and gender-matched control subjects (n = 12). Compared to the control group, Grade I meningioma patients showed increased serum levels of amphiregulin (AREG), CCL24, CD69, prolactin, EGF, HB-EGF, caspase-3, and decreased levels of VEGFD, TGF-α, E-Selectin, BAFF, IL-12, CCL9, and GH. For validation studies, we utilized an independent set of meningioma tumor tissue samples (Grade I, n = 20; Grade II, n = 10; Grade III, n = 6), and found that the expressions of amphiregulin and Caspase3 are significantly increased in all grades of meningiomas either at the transcriptional or protein level, respectively. In contrast, the gene expression of VEGF-D was significantly lower in Grade I meningioma tissue samples. Taken together, our study identifies a meningioma-specific protein signature in blood circulation of meningioma patients and highlights the importance of equilibrium between tumor-promoting factors and anti-tumor immunity.Peer reviewe

Analysis of Intracranial Meningioma Recurrence after Surgical Management

Background: Meningioma is one of the well-known common primary brain neoplasms that account for more than 20% of intracranial tumors. Intracranial meningioma recurrence after surgery has long been recognized, although the mechanism of recurrence remains unclear. Objective: To analyse impact of pre-operative and peri-operative measurements in relation to pathological outcome. Patients and Methods: Retrospectively analysed 72 patients with meningiomas (45) female and (27) male who were treated surgically and re-operated again at our Hawler Teaching Hospital and West Emergency Hospital from June 2017 until June 2021 in Erbil Governorate in Northern Iraq.  Clinical characteristics and demographics possibly associated with tumor recurrence were assessed, including gender, age, clinical symptoms, tumor location, pathology data, and radiotherapy and recurrence rate were closely studied. Results: A total of 72 cases with meningioma included in the research, in which 17 cases recurrent cases were observed, in total of 72 cases 58 were benign (Grade I), and 14 were atypical/ malignant (Grade II/III). The mean age of patients (SD) was ± 51.2 years and a follow-up duration of 4 years. Overall recurrence rates 23.6% with Male to Female ratio of 0.55:1. Age, and gender could not be demonstrated as significant association factor in tumor recurrence. Factors significantly associated with tumor relapse in the analysis were tumor location at the Foramen magnum and Optic Nerve, both being (50%). The rates of recurrence were significantly high when the degree of removal (by Simpsons Classification) was for grade three (50%) and for grade four and five (70%), compared with 6.3% and 8.8% for grade one or two, respectively. A high recurrence rate was detected when the adjuvant was not received compared with the patients who received radiotherapy. Majority of patients had better outcome. Conclusion: it was concluded from this study that Meningioma recurrence is well recognized and there are many factors including age, gender, extend of tumor resection, location, histological type of tumor and adjuvant therapy that would determine the pathological outcome and impact on patient’s life

A study of Progesterone receptor (PR) expression in Meningiomas, and its correlation with clinicopathological parameters

BACKGROUND: Meningiomas are the most common benign CNS neoplasms with higher prevalence in women. Clinical & epidemiological data reveal that Meningiomas are hormone sensitive tumours and they have been found to express hormonal receptors. AIMS AND OBJECTIVES: This study deals with the histomorphological characteristics and the immunohistochemical expression of Progesterone receptor (PR) in Meningiomas in correlation with various clinicopathological parameters. MATERIALS AND METHODS: This study analyzes the histopathological characteristics of 209 consecutively operated Meningiomas over a period of three years. Immunohistochemical study with monoclonal antibodies to PR was done only for 60 randomly selected cases. The PR expression in relation to age and sex of patient, site and various histopathological grades of the tumour, and their rates of recurrence were studied. RESULTS: Histopathological features such as small cell change, hypercellularity, sheet like pattern, nuclear pleomorphism, macronucleoli, high mitotic rates, necrosis and brain invasion were seen predominantly in high grade Meningiomas than benign Meningiomas. Immunohistochemical analysis revealed PR expression in 66.7% of cases. In comparison with grade I Meningiomas the PR expression in high grade and also recurrent Meningiomas were found to be from weak to absent, thereby showing a positive association between low rates of expression of PR and increased tumour aggressiveness. CONCLUSION: It is concluded that expression of progesterone receptors by the tumour in correlation with other histopathological features such as histological grade of the tumour, brain invasion and mitotic rates have been considered as a useful prognostic tool in assessing the behaviour of Meningiomas