scholarly journals MEOX2 Transcription Factor Is Involved in Survival and Adhesion of Glioma Stem-like Cells

Cancers ◽  
2021 ◽  
Vol 13 (23) ◽  
pp. 5943
Author(s):  
Gaëlle Tachon ◽  
Konstantin Masliantsev ◽  
Pierre Rivet ◽  
Amandine Desette ◽  
Serge Milin ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Lower Grade ◽  
Loss Of Function ◽  
Poor Overall Survival ◽  
Adhesion Properties ◽  
Glioma Recurrence ◽  
Lower Grade Glioma ◽  
Idh Mutations ◽  
Neuronal Lineage ◽  
The Impact

The high expression of MEOX2 transcription factor is closely associated with poor overall survival in glioma. MEOX2 has recently been described as an interesting prognostic biomarker, especially for lower grade glioma. MEOX2 has never been studied in glioma stem-like cells (GSC), responsible for glioma recurrence. The aim of our study was to investigate the role of MEOX2 in GSC. Loss of function approach using siRNA was used to assess the impact of MEOX2 on GSC viability and stemness phenotype. MEOX2 was localized in the nucleus and its expression was heterogeneous between GSCs. MEOX2 expression depends on the methylation state of its promoter and is strongly associated with IDH mutations. MEOX2 is involved in cell proliferation and viability regulation through ERK/MAPK and PI3K/AKT pathways. MEOX2 loss of function correlated with GSC differentiation and acquisition of neuronal lineage characteristics. Besides, inhibition of MEOX2 is correlated with increased expression of CDH10 and decreased pFAK. In this study, we unraveled, for the first time, MEOX2 contribution to cell viability and proliferation through AKT/ERK pathway and its potential involvement in phenotype and adhesion properties of GSC.

scholarly journals Voxel-wise radiogenomic mapping of tumor location with key molecular alterations in patients with glioma

2018 ◽  
Vol 20 (11) ◽  
pp. 1517-1524 ◽  
Author(s):  
Miguel Angel Tejada Neyra ◽  
Ulf Neuberger ◽  
Annekathrin Reinhardt ◽  
Gianluca Brugnara ◽  
David Bonekamp ◽  
...  
Keyword(s):  
Tumor Location ◽  
Molecular Characteristics ◽  
Consecutive Series ◽  
Lower Grade ◽  
Newly Diagnosed ◽  
Molecular Alterations ◽  
Lateral Ventricles ◽  
Lower Grade Glioma ◽  
Idh Mutations ◽  
The Impact

Abstract Background This study aims to evaluate the impact of tumor location on key molecular alterations on a single voxel level in patients with newly diagnosed glioma. Methods A consecutive series of n = 237 patients with newly diagnosed glioblastoma and n = 131 patients with lower-grade glioma was analyzed. Volumetric tumor segmentation was performed on preoperative MRI with a semi-automated approach and images were registered to the standard Montreal Neurological Institute 152 space. Using a voxel-based lesion symptom mapping (VLSM) analysis, we identified specific brain regions that were associated with tumor-specific molecular alterations. We assessed a predefined set of n = 17 molecular characteristics in the glioblastoma cohort and n = 2 molecular characteristics in the lower-grade glioma cohort. Permutation adjustment (n = 1000 iterations) was used to correct for multiple testing, and voxel t-values that were greater than the t-value in >95% of the permutations were retained in the VLSM results (α = 0.05, power > 0.8). Results Tumor location predilection for isocitrate dehydrogenase (IDH) mutant tumors was found in both glioblastoma and lower-grade glioma cohorts, each showing a concordant predominance in the frontal lobe adjacent to the rostral extension of the lateral ventricles (permutation-adjusted P = 0.021 for the glioblastoma and 0.013 for the lower-grade glioma cohort). Apart from that, the VLSM analysis did not reveal a significant association of the tumor location with any other key molecular alteration in both cohorts (permutation-adjusted P > 0.05 each). Conclusion Our study highlights the unique properties of IDH mutations and underpins the hypothesis that the rostral extension of the lateral ventricles is a potential location for the cell of origin in IDH-mutant gliomas.

scholarly journals RUNX1 and REXO2 are associated with the heterogeneity and prognosis of IDH wild type lower grade glioma

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Haiwei Wang ◽  
Xinrui Wang ◽  
Liangpu Xu ◽  
Ji Zhang ◽  
Hua Cao
Keyword(s):  
Transcription Factor ◽  
Low Frequency ◽  
Tumor Grade ◽  
The Cancer Genome Atlas ◽  
Lower Grade ◽  
Wild Type ◽  
Lower Grade Glioma ◽  
Cancer Genome Atlas ◽  
Worse Prognosis ◽  
Genome Atlas

AbstractBased on isocitrate dehydrogenase (IDH) alterations, lower grade glioma (LGG) is divided into IDH mutant and wild type subgroups. However, the further classification of IDH wild type LGG was unclear. Here, IDH wild type LGG patients in The Cancer Genome Atlas and Chinese Glioma Genome Atlas were divided into two sub-clusters using non-negative matrix factorization. IDH wild type LGG patients in sub-cluster2 had prolonged overall survival and low frequency of CDKN2A alterations and low immune infiltrations. Differentially expressed genes in sub-cluster1 were positively correlated with RUNX1 transcription factor. Moreover, IDH wild type LGG patients with higher stromal score or immune score were positively correlated with RUNX1 transcription factor. RUNX1 and its target gene REXO2 were up-regulated in sub-cluster1 and associated with the worse prognosis of IDH wild type LGG. RUNX1 and REXO2 were associated with the higher immune infiltrations. Furthermore, RUNX1 and REXO2 were correlated with the worse prognosis of LGG or glioma. IDH wild type LGG in sub-cluster2 was hyper-methylated. REXO2 hyper-methylation was associated with the favorable prognosis of LGG or glioma. At last, we showed that, age, tumor grade and REXO2 expression were independent prognostic factors in IDH wild type LGG.

scholarly journals Transcriptomic Analysis of Glioma Based on IDH Status Identifies ACAA2 as a Prognostic Factor in Lower Grade Glioma

2020 ◽  
Vol 2020 ◽  
pp. 1-8
Author(s):  
Chenxing Wu ◽  
Hongwang Song ◽  
Xiaojun Fu ◽  
Shouwei Li ◽  
Tao Jiang
Keyword(s):  
Prognostic Factor ◽  
Network Analysis ◽  
Targeted Therapies ◽  
Correlation Network ◽  
Lower Grade ◽  
Gene Expressions ◽  
Who Grade ◽  
Lower Grade Glioma ◽  
Idh Mutations ◽  
Weighted Correlation

Background. Glioma is the most common and lethal tumor in the central nervous system (CNS). More than 70% of WHO grade II/III gliomas were found to harbor isocitrate dehydrogenase (IDH) mutations which generated targetable metabolic vulnerabilities. Focusing on the metabolic vulnerabilities, some targeted therapies, such as NAMPT, have shown significant effects in preclinical and clinical trials. Methods. We explored the TCGA as well as CGGA database and analyzed the RNA-seq data of lower grade gliomas (LGG) with the method of weighted correlation network analysis (WGCNA). Differential expressed genes were screened, and coexpression relationships were grouped together by performing average linkage hierarchical clustering on the topological overlap. Clinical data were used to conduct Kaplan–Meier analysis. Results. In this study, we identified ACAA2 as a prognostic factor in IDH mutation lower grade glioma with the method of weighted correlation network analysis (WGCNA). The difference of ACAA2 gene expressions between the IDH wild-type (IDH-WT) group and the IDH mutant (IDH-MUT) group suggested that there may be different potential targeted therapies based on the fatty acid metabolic vulnerabilities, which promoted the personalized treatment for LGG patients.

scholarly journals Set-Wise Differential Interaction between Copy Number Alterations and Gene Expressions of Lower-Grade Glioma Reveals Prognosis-Associated Pathways

Entropy ◽  
2020 ◽  
Vol 22 (12) ◽  
pp. 1434
Author(s):  
Seong Beom Cho
Keyword(s):  
Density Estimation ◽  
Cancer Progression ◽  
Copy Number ◽  
Integrative Analysis ◽  
The Cancer Genome Atlas ◽  
Lower Grade ◽  
Gene Expressions ◽  
Survival Group ◽  
Lower Grade Glioma ◽  
The Impact

The integrative analysis of copy number alteration (CNA) and gene expression (GE) is an essential part of cancer research considering the impact of CNAs on cancer progression and prognosis. In this research, an integrative analysis was performed with generalized differentially coexpressed gene sets (gdCoxS), which is a modification of dCoxS. In gdCoxS, set-wise interaction is measured using the correlation of sample-wise distances with Renyi’s relative entropy, which requires an estimation of sample density based on omics profiles. To capture correlations between the variables, multivariate density estimation with covariance was applied. In the simulation study, the power of gdCoxS outperformed dCoxS that did not use the correlations in the density estimation explicitly. In the analysis of the lower-grade glioma of the cancer genome atlas program (TCGA-LGG) data, the gdCoxS identified 577 pathway CNAs and GEs pairs that showed significant changes of interaction between the survival and non-survival group, while other benchmark methods detected lower numbers of such pathways. The biological implications of the significant pathways were well consistent with previous reports of the TCGA-LGG. Taken together, the gdCoxS is a useful method for an integrative analysis of CNAs and GEs.

scholarly journals MPC-2 Clinical course and prognosis of lower-grade glioma, IDH wildtype and pTERT mutant

2021 ◽  
Vol 3 (Supplement_6) ◽  
pp. vi16-vi16
Author(s):  
Yoshinobu Takahashi ◽  
Hayato Takeuchi ◽  
Seisuke Tanigawa ◽  
Takanari Okamoto ◽  
Naoya Hashimoto
Keyword(s):  
Median Survival ◽  
Lower Grade ◽  
Diffuse Astrocytoma ◽  
Who Grade ◽  
Female Ratio ◽  
Astrocytic Glioma ◽  
Tert Promoter ◽  
Lower Grade Glioma ◽  
Idh Mutations ◽  
Astrocytic Gliomas

Abstract Background and Purpose: In the cIMPACT-Now update 3, it was proposed that grade 2 astrocytic gliomas without IDH-mutations and grade 3 astrocytic gliomas with TERT promoter mutations should be designated as diffuse IDH wildtype astrocytic glioma with molecular features of WHO grade IV glioblastoma. Therefore, we investigated whether this group of tumors actually corresponds to grade IV prognostically in cases that we encountered ourselves. Cases and Methods: Among the 65 patients having primary astrocytic glioma who were operated in our hospital from January 2016 to March 2021, the prognostic values of seven patients with lower-grade glioma, IDH wildtype, and pTERT mutant were investigated. Results: Among the seven patients, the median age was 59 years (50–66 years). Four of them had anaplastic astrocytoma, two had diffuse astrocytoma, and no tumor lesion could be identified upon histological examination for one patient. The male-to-female ratio was 1:6. MGMT methylation was observed in two patients (29%). The median survival was 20 months, with a significantly worse prognosis when compared with lower-grade glioma without the TERT promoter mutation (13 patients: median survival 40 months), but a better prognosis when compared with glioblastoma (45 patients: median survival 13 months) (Log-rank p = 0.0051). Conclusion: Although EGFR amplification, combined whole chromosome 7 gain, and whole chromosome 10 loss were not examined, the prognostic value of lower-grade glioma, IDH wildtype, and pTERT mutant was not as poor as that of glioblastoma. Further investigation is required to confirm whether these groups of tumors should be treated in the same way as grade IV glioblastoma.

TMOD-06. CREATION OF PATIENT-DERIVED LOWER GRADE GLIOMA ORGANOID MODELS FOR PERSONALIZED TREATMENT RESPONSE ASSESSMENT

2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi216-vi217
Author(s):  
Kalil Abdullah ◽  
Joseph Buehler ◽  
Cylaina Bird ◽  
MIlan Savani ◽  
Alex Sternisha ◽  
...  
Keyword(s):  
Treatment Response ◽  
Genetic Alterations ◽  
Lower Grade ◽  
High Grade ◽  
Who Grade ◽  
Oncology Research ◽  
Genetically Engineered Mice ◽  
Lower Grade Glioma ◽  
Idh Mutations

Abstract Creating in vitro models of lower grade glioma represents a major challenge in neuro-oncology research. There are few such models that are tractable and widely used, which has hindered understanding of the biology of these tumors. Recently, substantial progress has been made in generating patient-derived in vitro organoid models of high grade glioma, but modeling lower grade disease remains difficult. Based on our experience creating neurosphere cultures of lower grade astrocytomas from genetically engineered mice, we hypothesized that modifying patient-derived organoid generation protocols to incorporate physiological oxygen levels would allow establishment and propagation of lower grade glioma organoids. In this study, we show that this approach supports efficient organoid model generation from primary glioma specimens across all histological subtypes and tumor grades (WHO Grade I-IV, n = 20). These organoid models retain key characteristics of their respective parental tumors, including IDH mutations and other genetic alterations, metabolite profiles, intratumoral heterogeneity, cellular composition, and cytoarchitectural features. Importantly, lower grade glioma organoids can be cultured for months and reanimated after biobanking. Our high success rate ( >90%) in establishing organoid models from primary lower grade glioma tissue samples further highlighted opportunities for treatment response assessments. To perform longitudinal measurements of therapy-induced changes in glioma organoid viability, we designed a novel, non-invasive imaging assay (termed rapid apex imaging) to determine real-time treatment response in low and high grade gliomas. We evaluated longitudinal responses of glioblastoma and IDH1 R132H-positive Grade II astrocytoma organoids to temozolomide and olaparib with and without radiation treatment. We quantified topological changes in organoid structure by building a bioinformatics tool to translate imaging data into a cellularity metric as a biomarker of organoid response. Our work unveils an effective new method to create in vitro, personalized models of lower grade glioma that supports elucidation of treatment sensitivity profiles.

scholarly journals Modulation of transcriptional activity in brain lower grade glioma by alternative splicing

2018 ◽  
Author(s):  
Jin Li ◽  
Yang Wang ◽  
Xianglian Meng ◽  
Hong Liang
Keyword(s):  
Transcription Factor ◽  
Transcriptional Regulation ◽  
Alternative Splicing ◽  
Structural Features ◽  
Vital Role ◽  
Lower Grade ◽  
Exon Inclusion ◽  
Gene Transcriptional Regulation ◽  
Lower Grade Glioma

Proteins that modify the activity of transcription factor (TF), often called modulators, play a vital role in gene transcriptional regulation. Alternative splicing is a critical step of gene processing and it can modulate gene function by adding or removing certain protein domains, and therefore influences the activity of a protein. The objective of this study is to investigate the role of alternative splicing in modulating the transcriptional regulation in brain lower grade glioma (LGG), especially transcription factor ELK1, which is closely related to various diseases, including Alzheimer’s disease and down syndrome. Results showed that changes in the exon inclusion ratio of proteins APP and STK16 are associated with changes in the expression correlation between ELK1 and its targets. Meanwhile, the structural features of the two modulators are strongly associated with the pathological impact of exon inclusion. Our analysis suggests, protein in different splicing level could play different functions on transcription factors, hence induces multiple genes dysregulation.

scholarly journals Modulation of transcriptional activity in brain lower grade glioma by alternative splicing

2018 ◽  
Author(s):  
Jin Li ◽  
Yang Wang ◽  
Xianglian Meng ◽  
Hong Liang
Keyword(s):  
Transcription Factor ◽  
Transcriptional Regulation ◽  
Alternative Splicing ◽  
Structural Features ◽  
Vital Role ◽  
Lower Grade ◽  
Exon Inclusion ◽  
Gene Transcriptional Regulation ◽  
Lower Grade Glioma

Proteins that modify the activity of transcription factor (TF), often called modulators, play a vital role in gene transcriptional regulation. Alternative splicing is a critical step of gene processing and it can modulate gene function by adding or removing certain protein domains, and therefore influences the activity of a protein. The objective of this study is to investigate the role of alternative splicing in modulating the transcriptional regulation in brain lower grade glioma (LGG), especially transcription factor ELK1, which is closely related to various diseases, including Alzheimer’s disease and down syndrome. Results showed that changes in the exon inclusion ratio of proteins APP and STK16 are associated with changes in the expression correlation between ELK1 and its targets. Meanwhile, the structural features of the two modulators are strongly associated with the pathological impact of exon inclusion. Our analysis suggests, protein in different splicing level could play different functions on transcription factors, hence induces multiple genes dysregulation.

scholarly journals Isocitrate Dehydrogenase Mutations in Glioma: Genetics, Biochemistry, and Clinical Indications

Biomedicines ◽  
2020 ◽  
Vol 8 (9) ◽  
pp. 294 ◽  
Author(s):  
Yang Liu ◽  
Fengchao Lang ◽  
Fu-Ju Chou ◽  
Kareem A. Zaghloul ◽  
Chunzhang Yang
Keyword(s):  
Enzyme Activity ◽  
Isocitrate Dehydrogenase ◽  
Therapeutic Efficacy ◽  
Cancer Biology ◽  
Lower Grade ◽  
Idh Mutation ◽  
Genetic Characteristics ◽  
Lower Grade Glioma ◽  
Idh Mutations ◽  
Secondary Glioblastomas

Mutations in isocitrate dehydrogenase (IDH) are commonly observed in lower-grade glioma and secondary glioblastomas. IDH mutants confer a neomorphic enzyme activity that converts α-ketoglutarate to an oncometabolite D-2-hydroxyglutarate, which impacts cellular epigenetics and metabolism. IDH mutation establishes distinctive patterns in metabolism, cancer biology, and the therapeutic sensitivity of glioma. Thus, a deeper understanding of the roles of IDH mutations is of great value to improve the therapeutic efficacy of glioma and other malignancies that share similar genetic characteristics. In this review, we focused on the genetics, biochemistry, and clinical impacts of IDH mutations in glioma.

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