IDH mutation status and role of WHO grade and mitotic index in overall survival in grade II–III diffuse gliomas

Abstract Background Vascular gene expression patterns in lower-grade gliomas (LGGs; diffuse World Health Organization [WHO] grades II–III gliomas) have not been thoroughly investigated. The aim of this study was to molecularly characterize LGG vessels and determine if tumor isocitrate dehydrogenase (IDH) mutation status affects vascular phenotype. Methods Gene expression was analyzed using an in-house dataset derived from microdissected vessels and total tumor samples from human glioma in combination with expression data from 289 LGG samples available in the database of The Cancer Genome Atlas. Vascular protein expression was examined by immunohistochemistry in human brain tumor tissue microarrays (TMAs) representing WHO grades II–IV gliomas and nonmalignant brain samples. Regulation of gene expression was examined in primary endothelial cells in vitro. Results Gene expression analysis of WHO grade II glioma indicated an intermediate stage of vascular abnormality, less severe than that of glioblastoma vessels but distinct from normal vessels. Enhanced expression of laminin subunit alpha 4 (LAMA4) and angiopoietin 2 (ANGPT2) in WHO grade II glioma was confirmed by staining of human TMAs. IDH wild-type LGGs displayed a specific angiogenic gene expression signature, including upregulation of ANGPT2 and serpin family H (SERPINH1), connected to enhanced endothelial cell migration and matrix remodeling. Transcription factor analysis indicated increased transforming growth factor beta (TGFβ) and hypoxia signaling in IDH wild-type LGGs. A subset of genes specifically induced in IDH wild-type LGG vessels was upregulated by stimulation of endothelial cells with TGFβ2, vascular endothelial growth factor, or cobalt chloride in vitro. Conclusion IDH wild-type LGG vessels are molecularly distinct from the vasculature of IDH-mutated LGGs. TGFβ and hypoxia-related signaling pathways may be potential targets for anti-angiogenic therapy of IDH wild-type LGG.

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The Role of Adjuvant Radiotherapy in Atypical (Who Grade II) Meningiomas: Meta-Analysis and Systematic Review of Literature

Journal of Neurological Surgery Part B Skull Base ◽

10.1055/s-0035-1546700 ◽

2015 ◽

Vol 76 (S 01) ◽

Cited By ~ 1

Author(s):

Maged Fam ◽

Sam Eljamel

Keyword(s):

Systematic Review ◽

Adjuvant Radiotherapy ◽

Meta Analysis ◽

Review Of Literature ◽

Who Grade ◽

Grade Ii

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Influence of VEGF-A, VEGFR-1-3, and neuropilin 1-2 on progression-free: and overall survival in WHO grade II and III meningioma patients

Journal of Molecular Histology ◽

10.1007/s10735-020-09940-2 ◽

2021 ◽

Vol 52 (2) ◽

pp. 233-243

Author(s):

Simon Bernatz ◽

Daniel Monden ◽

Florian Gessler ◽

Tijana Radic ◽

Elke Hattingen ◽

...

Keyword(s):

Overall Survival ◽

Tumor Cells ◽

Progression Free Survival ◽

Staining Intensity ◽

Who Grade ◽

Positive Correlation ◽

Protein Levels ◽

Angiogenic Therapy ◽

Neuropilin 1 ◽

Grade Ii

AbstractHigher grade meningiomas tend to recur. We aimed to evaluate protein levels of vascular endothelial growth factor (VEGF)-A with the VEGF-receptors 1-3 and the co-receptors Neuropilin (NRP)-1 and -2 in WHO grade II and III meningiomas to elucidate the rationale for targeted treatments. We investigated 232 specimens of 147 patients suffering from cranial meningioma, including recurrent tumors. Immunohistochemistry for VEGF-A, VEGFR-1-3, and NRP-1/-2 was performed on tissue micro arrays. We applied a semiquantitative score (staining intensity x frequency). VEGF-A, VEGFR-1-3, and NRP-1 were heterogeneously expressed. NRP-2 was mainly absent. We demonstrated a significant increase of VEGF-A levels on tumor cells in WHO grade III meningiomas (p = 0.0098). We found a positive correlation between expression levels of VEGF-A and VEGFR-1 on tumor cells and vessels (p < 0.0001). In addition, there was a positive correlation of VEGF-A and VEGFR-3 expression on tumor vessels (p = 0.0034). VEGFR-2 expression was positively associated with progression-free survival (p = 0.0340). VEGF-A on tumor cells was negatively correlated with overall survival (p = 0.0084). The VEGF-A-driven system of tumor angiogenesis might still present a suitable target for adjuvant therapy in malignant meningioma disease. However, its role in malignant tumor progression may not be as crucial as expected. The value of comprehensive testing of the ligand and all receptors prior to administration of anti-angiogenic therapy needs to be evaluated in clinical trials.

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Identification of WHO II/III gliomas by 16 prognostic-related gene signatures using machine learning methods

Current Medicinal Chemistry ◽

10.2174/0929867328666210827103049 ◽

2021 ◽

Vol 28 ◽

Author(s):

YaMeng Wu ◽

Yu Sa ◽

Yu Guo ◽

QiFeng Li ◽

Ning Zhang

Keyword(s):

Neural Network ◽

Machine Learning ◽

Overall Survival ◽

High Risk ◽

Who Grade ◽

Machine Learning Methods ◽

Medium Risk ◽

Grade Ii ◽

Fully Connected ◽

Genome Atlas

Background: It is found that the prognosis of gliomas of the same grade has large differences among World Health Organization(WHO) grade II and III in clinical observation. Therefore, a better understanding of the genetics and molecular mechanisms underlying WHO grade II and III gliomas is required, with the aim of developing a classification scheme at the molecular level rather than the conventional pathological morphology level. Method: We performed survival analysis combined with machine learning methods of Least Absolute Shrinkage and Selection Operator using expression datasets downloaded from the Chinese Glioma Genome Atlas as well as The Cancer Genome Atlas. Risk scores were calculated by the product of expression level of overall survival-related genes and their multivariate Cox proportional hazards regression coefficients. WHO grade II and III gliomas were categorized into the low-risk subgroup, medium-risk subgroup, and high-risk subgroup. We used the 16 prognostic-related genes as input features to build a classification model based on prognosis using a fully connected neural network. Gene function annotations were also performed. Results: The 16 genes (AKNAD1, C7orf13, CDK20, CHRFAM7A, CHRNA1, EFNB1, GAS1, HIST2H2BE, KCNK3, KLHL4, LRRK2, NXPH3, PIGZ, SAMD5, ERINC2, and SIX6) related to the glioma prognosis were screened. The 16 selected genes were associated with the development of gliomas and carcinogenesis. The accuracy of an external validation data set of the fully connected neural network model from the two cohorts reached 95.5%. Our method has good potential capability in classifying WHO grade II and III gliomas into low-risk, medium-risk, and high-risk subgroups. The subgroups showed significant (P<0.01) differences in overall survival. Conclusion: This resulted in the identification of 16 genes that were related to the prognosis of gliomas. Here we developed a computational method to discriminate WHO grade II and III gliomas into three subgroups with distinct prognoses. The gene expression-based method provides a reliable alternative to determine the prognosis of gliomas.

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PATH-26. EVALUATING THE DISTRIBUTION AND PROGNOSIS OF IMMUNE CELL SIGNATURES OF THE TUMOR MICRO-ENVIRONMENT IN DIFFUSE GLIOMAS

Neuro-Oncology ◽

10.1093/neuonc/noab196.478 ◽

2021 ◽

Vol 23 (Supplement_6) ◽

pp. vi120-vi120

Author(s):

Bharati Mehani ◽

Saleembhasha Asanigari ◽

Hye-Jung Chung ◽

Kenneth Aldape

Keyword(s):

Gene Expression ◽

Single Cell ◽

Immune Cell ◽

Tumor Grade ◽

Cell Types ◽

Idh Mutation ◽

Mutation Status ◽

Cluster Analyses ◽

Diffuse Gliomas ◽

Cell Expression

Abstract The tumor micro-environment (TME) plays an important role in the biology of cancer, including gliomas. Single cell studies have highlighted the role of specific TME components in gliomas, and the methods to deconvolve bulk profiling data may serve to complement these studies on clinically annotated tumors. In this study, we estimated cell type proportions in 3 large glioma datasets (TCGA, CGGA-325, CGGA-693) using CIBERSORTx. Using a signature matrix comprising 22 immune cell types, we identified IDH mutation status-specific immune cell distributions and found that the proportions of 10 cell types were significantly different between IDHmut and IDHwt tumors across the 3 datasets. Looking further within IDHmut tumors, we found that monocytes were enriched in 1p/19q non-co-deleted tumors across the 3 glioma datasets, consistent with prior single cell studies. We then examined estimated gene expression among immune cell types relative to IDH mutation status and found clear separation of gene expression in 15 of 22 cell types in all 3 datasets. When we applied these 22 gene expression signatures in each tumor sample onto cluster-of-cluster analyses to identify tumor groups with distinct immune signature patterns, we found that samples were distributed largely according to the IDH status in all 3 datasets, confirming that immune cell expression is distinct based on IDH status. Among IDH-specific groups, cluster-of-cluster analyses showed that immune cell-based cluster groups had distinct survival outcomes, and that IDHwt samples were distributed significantly based on tumor grades as well as based on EGFR overexpression. Among IDHmut tumors, the distributions of tumor grade and 1p/19q co-deletion status were significantly different in the immune-based clusters in 2 of the 3 datasets examined. Overall, these results highlight the biological and clinical significance of the immune cell environment in gliomas, including distinctions based on IDH mutation status as well as prognosis within IDH-specific groups.

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Role of adjuvant radiotherapy in atypical (WHO grade II) and anaplastic (WHO grade III) meningiomas: a systematic review

Clinical & Translational Oncology ◽

10.1007/s12094-020-02434-3 ◽

2020 ◽

Cited By ~ 1

Author(s):

P. D. Delgado-López ◽

E. M. Corrales-García

Keyword(s):

Systematic Review ◽

Adjuvant Radiotherapy ◽

Who Grade ◽

Grade Ii ◽

Who Grade Iii ◽

Grade Iii

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P14.95 Is the pathological-grade relevant in “IDH-wild type, TERT-mutant” diffuse-gliomas? An analysis in 147 patients

Neuro-Oncology ◽

10.1093/neuonc/noz126.330 ◽

2019 ◽

Vol 21 (Supplement_3) ◽

pp. iii90-iii90

Author(s):

A E Danyeli ◽

C B Akyerli ◽

A Dinçer ◽

E Coşgun ◽

U Abacıoğlu ◽

...

Keyword(s):

Overall Survival ◽

Progression Free Survival ◽

Genetic Alterations ◽

Lower Grade ◽

Wild Type ◽

Ki 67 ◽

Who Grade ◽

Free Survival ◽

Tert Promoter ◽

Diffuse Gliomas

Abstract BACKGROUND Although the word “glioblastoma” still denotes a grade-IV pathology, basic molecular studies have clearly indicated that a significant proportion of lower-grade gliomas harbor genetic alterations typical of glioblastomas. Based on these findings cIMPACT-NOW update 3 has defined an entity called the “diffuse astrocytic glioma, IDH-wildtype, with molecular features of glioblastoma, WHO grade IV”. A TERT-promoter mutation is one of these typical molecular markers of glioblastomas. In this study we analyzed IDH-wild type, TERT-mutant diffuse gliomas of different pathological grades to look for differences in demographic, clinical and survival characteristics. MATERIAL AND METHODS 147 adult hemispheric diffuse-gliomas with wild-type IDH1/2 and mutant TERT-promoter (C228T or C250T) were retrospectively analyzed. Primary thalamic, cerebellar brainstem or spinal cases were excluded. 126 (86%), 16(11%) and 5(3%) patients were WHO grade IV, III and II respectively. After surgical treatment or stereotactic biopsy all patients underwent chemoradiation. Median follow-up was 16mo (1–110). Tumors of different grades were compared for age, gender, multifocality, gliomatosis pattern, Ki-67 index, progression-free survival and overall-survival. RESULTS Mean age at presentation for grade II, III and IV were comparable (58.1, 58 and 58.1; ANOVA, p=0.72). There was a slight male predominance in both lower-grades and WHO-grade IV (M:F ratios 1.625 and 1.74). Mean Ki-67 index was significantly higher in higher grades (0.06, 0.14 and 0.25 for grades II, III and IV; ANOVA, p=0.001). Multifocality was comparable (chi-sq, p=1) in lower-grades (3/21; 14.3%) vs. WHO-grade IV (18/126; 14.3%). Gliomatosis pattern was comparable (chi-sq, p=0.095) in lower-grades (2/21; 9.5%) vs. (3/126; 2.3%). Median recurrence free survival (RFS) was 16 months (0–63) in lower-grades and 8months (1–50) in WHO-grade IV. PFS was significantly different between 3 WHO-grades (Log rank, p=0.007) and also between lower-grades and WHO-grade IV (Log rank, p=0.002). Median overall survival was 26 months(2–110) in lower-grades and 15mo(1–91) in WHO-grade IV. OS was significantly different between 3 WHO-grades (Log rank, p=0.014) and also between lower-grades and WHO-grade IV (Log rank, p=0.007). CONCLUSION Increasing pathological grades of hemispheric “IDH-wild type, TERT-mutant diffuse gliomas” have similar demographic and clinical characteristics but incrasing proliferation indices, decrasing progression free survival and shorter overall survival. The findings may be suggesitve of different grades of one common tumor entity.

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