👤 Sophie Kafka

Epithelial to mesenchymal transition (EMT) plays a critical role in tumor progression and metastasis, including in gliomas. To examine and interpret data on major genes involved in EMT and associate their changes with low-grade (LGG) and/or high-grade (HGG) gliomas, data from the cBioPortal-a publicly available database for tumor genomics and transcriptomics, were collected for 13 genes: CDH1, CDH2, CTNNB1, LEF1, NOTCH1, SNAI1, SNAI2, SOX2, TJP1/ZO1, TWIST1, VIM, ZEB1, and ZEB2. The dataset included mutations, copy number alterations (CNA), and changes in transcript levels reported for each gene. The genes were additionally validated by gene expression on the GlioVis portal, STRING protein network analysis, survival analysis, and experimentally with qRT-PCR. Glioblastoma and diffuse glioma harbored changes in all 13 analyzed genes, while anaplastic oligodendroglioma and anaplastic astrocytoma in 46.15%, oligodendroglioma in 23.08%, and oligoastrocytoma in 15.38%. NOTCH1 and SOX2 were most affected by changes. The NOTCH1 gene was statistically more frequently changed compared to CDH1, CTNNB1, and ZEB1 (p < 0.05). The virtual study showed that alterations in NOTCH1 and LEF1 were associated with LGG, while alterations in CDH1, CTNNB1, TJP1, TWIST1, SOX2, VIM, ZEB1, and ZEB2 were associated with HGG. Differential expression analysis stratified for IDH1 mutations showed that IDH1-mutant glioblastoma had significantly lower CDH2, LEF1 and SNAI1 expression, and higher ZEB1. Gene expression in different glioblastoma subtypes showed that the TJP1/ZO1 gene was associated with the classical subtype, while ZEB2 was associated with the proneural subtype. qRT-PCR confirmed GlioVis mRNA expression data for NOTCH1, SOX2, CDH1, CTNNB1, TJP1/ZO-1, VIM, TWIST1, and partially for SNAI1 (SNAIL), SNAI2, and CDH2. Our study shows consistent changes in genes involved in EMT in gliomas of different grades. Additional research is needed to confirm the knowledge brought by this study. Show less

Postreplicative mismatch repair safeguards the stability of our genome. The defects in its functioning will give rise to microsatellite instability. In this study, 50 meningiomas were investigated for microsatellite instability. Two major mismatch repair genes, MLH1 and MSH2, were analyzed using microsatellite markers D1S1611 and BAT26 amplified by polymerase chain reaction and visualized by gel electrophoresis on high-resolution gels. Furthermore, genes DVL3 (D3S1262), AXIN1 (D16S3399), and CDH1 (D16S752) were also investigated for microsatellite instability. Our study revealed constant presence of microsatellite instability in meningioma patients when compared to their autologous blood DNA. Altogether 38% of meningiomas showed microsatellite instability at one microsatellite locus, 16% on two, and 13.3% on three loci. The percent of detected microsatellite instability for MSH2 gene was 14%, and for MLH1, it was 26%, for DVL3 22.9%, for AXIN1 17.8%, and for CDH1 8.3%. Since markers also allowed for the detection of loss of heterozygosity, gross deletions of MLH1 gene were found in 24% of meningiomas. Genetic changes between MLH1 and MSH2 were significantly positively correlated (p = 0.032). We also noted a positive correlation between genetic changes of MSH2 and DVL3 genes (p = 0.034). No significant associations were observed when MLH1 or MSH2 was tested against specific histopathological meningioma subtype or World Health Organization grade. However, genetic changes in DVL3 were strongly associated with anaplastic histology of meningioma (χ Show less

Tumor suppressor gene AXIN1 is an inhibitor of Wnt signaling pathway. It down-regulates the pathway's main signaling effector molecule, beta-catenin, in an AXIN-based destruction complex. In the present study we investigated the involvement of AXIN1 in intracranial meningioma. Loss of heterozygosity and microsatellite instability analyses were performed. The consequences of genetic changes on protein expression levels were studied in the same patients by immunohistochemistry. Allelic deletions of AXIN1 gene were found in 21.1% of meningiomas. Microsatellite instability was also observed in 5.3% of cases. Weak or lack of AXIN1 expression was found in 21.9% of meningiomas. We found strong statistical correlations between cytoplasmic localization of AXIN1 and its weak expression and also between the simultaneous cytoplasmic and nuclear localizations and moderate and strong expression levels (p<0.000). The findings on AXIN1 were compared to concomitant expression of APC, beta-catenin and E-cadherin in the same patients by Chi-Square tests and Pearson's correlations. Analysis revealed that AXIN1 genetic changes were significantly associated to lack of the expression of APC and presence of mutant APC proteins (p<0.018). Moderate and strong cytoplasmic and nuclear AXIN1 expressions were positively correlated to strong expression of E-cadherin (p<0.05). Our findings on genetic changes and expression levels of AXIN1 bring novel data on its involvement in meningeal brain tumors and reveal AXIN1's relation to specific Wnt molecules. Show less

Research over the last decade recognized the importance of novel molecular pathways in pathogenesis of intracranial meningiomas. In this review, we focus on human brain tumours meningiomas and the involvement of Wnt signalling pathway genes and proteins in this common brain tumour, describing their known functional effects. Meningiomas originate from the meningeal layers of the brain and the spinal cord. Most meningiomas have benign clinical behaviour and are classified as grade I by World Health Organization (WHO). However, up to 20% histologically classified as atypical (grade II) or anaplastic (grade III) are associated with higher recurrent rate and have overall less favourable clinical outcome. Recently, there is emerging evidence that multiple signalling pathways including Wnt pathway contribute to the formation and growth of meningiomas. In the review we present the synopsis on meningioma histopathology and genetics and discuss our research regarding Wnt in meningioma. Epithelial-to-mesenchymal transition, a process in which Wnt signalling plays an important role, is shortly discussed. Show less