scholarly journals IDH mutation status is associated with distinct vascular gene expression signatures in lower-grade gliomas

2018 ◽  
Vol 20 (11) ◽  
pp. 1505-1516 ◽  
Author(s):  
Lei Zhang ◽  
Liqun He ◽  
Roberta Lugano ◽  
Kenney Roodakker ◽  
Michael Bergqvist ◽  
...  
Keyword(s):  
Gene Expression ◽  
Endothelial Cells ◽  
Lower Grade ◽  
Idh Mutation ◽  
Wild Type ◽  
Who Grade ◽  
Mutation Status ◽  
Grade Ii ◽  
Grade Ii Glioma

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.

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

2015 ◽  
Vol 129 (4) ◽  
pp. 585-596 ◽  
Author(s):  
Adriana Olar ◽  
Khalida M. Wani ◽  
Kristin D. Alfaro-Munoz ◽  
Lindsey E. Heathcock ◽  
Hinke F. van Thuijl ◽  
...  
Keyword(s):  
Overall Survival ◽  
Mitotic Index ◽  
Idh Mutation ◽  
Who Grade ◽  
Mutation Status ◽  
Diffuse Gliomas ◽  
Grade Ii

scholarly journals Preferential Tumor Localization in Relation to 18F-FDOPA Uptake for Lower-Grade Gliomas

2021 ◽  
Author(s):  
Hiroyuki Tatekawa ◽  
Hiroyuki Uetani ◽  
Akifumi Hagiwara ◽  
Jingwen Yao ◽  
Talia C. Oughourlian ◽  
...  
Keyword(s):  
Frontal Lobe ◽  
Standardized Uptake Value ◽  
Tumor Segmentation ◽  
Tumor Localization ◽  
Lower Grade ◽  
Wild Type ◽  
Who Grade ◽  
Positron Emission ◽  
Grade Ii ◽  
Differential Involvement

Abstract PurposeAlthough tumor localization and 3,4-dihydroxy-6-18F-fluoro-L-phenylalanine (FDOPA) uptake may have an association, preferential tumor localization in relation to FDOPA uptake is yet to be investigated in lower-grade gliomas (LGGs). This study aimed to identify differences in the frequency of tumor localization between FDOPA hypometabolic and hypermetabolic LGGs using a probabilistic radiographic atlas.MethodsFifty-one patients with newly diagnosed LGG (WHO grade II, 29; III, 22; isocitrate dehydrogenase wild-type, 21; mutant 1p19q non-codeleted ,16; mutant codeleted, 14) who underwent FDOPA positron emission tomography (PET) were retrospectively selected. Semiautomated tumor segmentation on FLAIR was performed. Patients with LGGs were separated into two groups (FDOPA hypometabolic and hypermetabolic LGGs) according to the normalized maximum standardized uptake value of FDOPA PET (a threshold of the uptake in the striatum) within the segmented regions. Spatial normalization procedures to build a 3D MRI-based atlas using each segmented region were validated by an analysis of differential involvement statistical mapping.ResultsSuperimposition of regions of interest showed a high number of hypometabolic LGGs localized in the frontal lobe, while a high number of hypermetabolic LGGs was localized in the insula, putamen, and temporal lobe. The statistical mapping revealed that hypometabolic LGGs occurred more frequently in the superior frontal gyrus (close to the supplementary motor area), while hypermetabolic LGGs occurred more frequently in the insula. ConclusionRadiographic atlases revealed preferential frontal lobe localization for FDOPA hypometabolic LGGs, which may be associated with relatively early detection.

scholarly journals Random Forest Model For Predicting IDH1 Gene Expression Based on Volumetric Texture Parameters of WHO Grade II/III Glioma and Peritumoral EdemaRandom Forest Model for Predicting IDH1 Gene Expression Based on Volumetric Texture Parameters of WHO Grade II/III Glioma and Peritumoral Edema

2021 ◽  
Author(s):  
Wenting Lan ◽  
Zhan Feng ◽  
Yan Zhang ◽  
ZhengYa Zhao ◽  
Yi Huang ◽  
...  
Keyword(s):  
Gene Expression ◽  
Random Forest ◽  
Random Forest Model ◽  
Peritumoral Edema ◽  
Wild Type ◽  
Who Grade ◽  
Forest Model ◽  
Texture Parameters ◽  
Grade Ii ◽  
Volumetric Texture

Abstract Background: The incidence of Isocitrate dehydrogenase (IDH) gene mutation had closed contact with the development and prognosis of WHO grade II/III glioma. This study aims to establish and evaluate the predicting random Forest model for IDH1 gene mutation based on parenchyma and peritumoral edema ADC image texture parameters of WHO grade II/III glioma. Materials and Methods: 146 patients (77 males and 69 females) with histologically confirmed anaplastic glioma were divided into training and validation groups in a ratio of 7:3 according to the requirements of Random Forest Model. The training group consisted of 102 patients (42 IDH1 mutant and 60 wild type) and the validation group included 44 patients (18 IDH1 mutant and 26 wild type). Conventional MRI features of two independent samples (IDH1 mutant and wild type) were evaluated by the Visually Accessible Rembrandt Images (VASARI) scoring system, Texture analysis (TA) of ADC image was based on the entire tumor volume and peritumoral edema and was used as Principal component analysis (PCA) to screen texture features labels. Random forest diagnosis models (VASARI+TumorADC、VASARI+TumorADC+EdemaADC) were constructed on the basis of morphological single-factor variables, texture feature labels. Result: The diagnostic accuracy of the random forest diagnosis model (VASARI+Tumor ADC) was 71.5%, the specificity was 75.40%, and the AUC was 0.769, The model (VASARI+TumorADC +peritumoral edema ADC ) was 80.9%, 79.5% ,and 0.819 correspondingly. Conclusion: The texture parameters of peritumoral edema ADC image were non-invasive markers to predict IDH1 mutational status and they have played a certain role in improving the efficiency of diagnostic model.

Abstract 5270: IDH mutation status and role of WHO grade and mitotic index in overall survival in grade II-III diffuse gliomas

2015 ◽  
Author(s):  
Adriana Olar ◽  
Khalida Wani ◽  
Kristin Diefes ◽  
Lindsey Heathcock ◽  
Hinke van Thuijl ◽  
...  
Keyword(s):  
Overall Survival ◽  
Mitotic Index ◽  
Idh Mutation ◽  
Who Grade ◽  
Mutation Status ◽  
Diffuse Gliomas ◽  
Grade Ii

scholarly journals P14.23 Risk of venous thromboembolism (VTE) in grade II-IV gliomas as a function of molecular subtype

2019 ◽  
Vol 21 (Supplement_3) ◽  
pp. iii71-iii72
Author(s):  
M Diaz ◽  
J Jo ◽  
D Schiff
Keyword(s):  
Molecular Subtype ◽  
Methylation Status ◽  
Promoter Hypermethylation ◽  
Molecular Testing ◽  
Lower Grade ◽  
Idh Mutation ◽  
Mgmt Methylation ◽  
Who Grade ◽  
Grade Ii ◽  
Grade Iii

Abstract BACKGROUND VTE affects up to 30% of patients with glioblastoma (GBM, WHO grade IV), but little is known about its incidence in lower-grade gliomas (LGG, WHO grade II-III). It has been suggested that isocitrate dehydrogenase (IDH) mutation status dramatically decreases the incidence of VTE in glioma patients, through a combination of F3 promoter hypermethylation leading to lower expression of the procoagulant protein tissue factor, and an increased production of D-2-hydroxyglutarate, which has anticoagulant properties (Unruh et al, 2016). Our objective was to determine the incidence of VTE in LGG and stratify VTE risk by molecular subtype in gliomas grade II-IV. MATERIAL AND METHODS We performed a retrospective analysis of 590 glioma patients with molecular testing seen at our institution (UVa) from January 2005 to August 2017. We divided LGG patients into 3 groups: IDH-wildtype (IDHwt); IDH-mutant (IDHmt), 1p/19q-codeleted; and IDHmt, 1p/19q-intact. GBM patients were divided according to MGMT methylation status. Estimates of cumulative incidence of VTE were calculated with death as competing risk, and significance testing was determined using the Fine and Gray model. RESULTS Of 256 LGG patients (147 grade II and 109 grade III), 81 were IDHwt, 113 IDHmt and 1p/19q-codeleted, and 62 IDHmt and 1p/19q-intact. There were 334 GBM patients, with MGMT methylation status available in 263 (98 (37%) methylated and 165 (63%) unmethylated). With a median follow-up of 545 days, the overall incidence of VTE was 8.2% for grade II, 9.2% for grade III and 30.5% for grade IV. The 6-, 12- and 24-month VTE incidence was 4.1%, 4.8% and 5.4% respectively for grade II, 4.6%, 7.3% and 9.2% for grade III and 23.1%, 26.6% and 29% for grade IV. In LGG patients, VTE incidence was slightly higher in IDHwt tumors (11.1%) vs IDHmt, 1p/19q-codeleted (8.8%) and IDHmt, 1p/19q-intact tumors (4.8%). However, this difference was not statistically significant (IDHwt vs IDHmt, 1p/19q-codeleted, sub-distribution hazard ratio (SHR)=1.67, 95% CI=0.59–4.72; IDHwt vs IDHmt, 1p/19q-intact, SHR=1.87, 95% CI=0.54–6.53). In GBM patients, there was no difference in the VTE incidence according to MGMT methylation status (SHR=0.99, 95% CI=0.64–1.54). CONCLUSION In our cohort, the risk of VTE in GBM patients was consistent with historical data; patients with LGG also had a higher VTE risk compared to the general population. In contrast to other retrospective studies in which the incidence of VTE for grade II-IV IDHmt gliomas was 0% (Unruh et al, 2016; Nazari et al, 2018), our data suggest that VTEs do occur in IDHmt LGG patients, although at a lower rate than in IDHwt. MGMT methylation does not seem to influence the incidence of VTE. VTE risk stratification in GBM patients based on IDH mutation is forthcoming.

Gene expression signature to predict radiation response in lower-grade gliomas.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 2019-2019
Author(s):  
David C Qian ◽  
Joseph A. Marascio ◽  
Stewart G. Neill ◽  
Kimberly B. Hoang ◽  
Jeffrey J. Olson ◽  
...  
Keyword(s):  
Gene Expression ◽  
Lower Grade ◽  
Training Set ◽  
Who Grade ◽  
Internal Validation ◽  
Expression Levels ◽  
Expression Signature ◽  
Grade Ii ◽  
Validation Set ◽  
Grade Iii

2019 Background: Standard of care for lower-grade glioma (LGG) is maximal safe resection and risk-adaptive adjuvant therapy. While patients who benefit the most from adjuvant chemotherapy have been elucidated in prospective randomized studies, comparable insights for adjuvant radiotherapy (RT) are lacking. We sought to identify and validate patterns of gene expression that are associated with differential outcomes among LGG patients treated by RT from two large genomics databases. Methods: Patients from The Cancer Genome Atlas (TCGA) with LGG (WHO grade II–III gliomas) treated by surgery and adjuvant RT were randomized 1:1 to a training set or an internal validation set. Using patients in the training set, association between gene expression from resected tumor and progression-free survival (PFS) as well as overall survival (OS) was evaluated with adjustment for clinicopathologic covariates. A genomic risk score (GRS) was then constructed from the expression levels of top genes also screened for involvement in glioma carcinogenesis. The prognostic value of GRS was subsequently validated in the internal validation set of TCGA and a second distinct database, compiled by the Chinese Glioma Genome Association (CGGA). Results: From TCGA, 289 patients with LGG received adjuvant RT alone (38 grade II, 30 grade III) or chemoradiotherapy (CRT) (51 grade II, 170 grade III) between 2009 and 2015. From CGGA, 178 patients with LGG received adjuvant RT alone (40 grade II, 13 grade III) or CRT (41 grade II, 84 grade III) between 2004 and 2016. The genes comprising GRS are MAP3K15, MAPK10, CCL3, CCL4, and ADAMTS1, involved in MAP kinase activity, T cell chemotaxis, and cell cycle transition. High GRS, defined as having a GRS in the top third, was significantly associated with worse outcomes independent of age, sex, glioma histology, WHO grade, IDH mutation, 1p/19q co-deletion, and chemotherapy status in the training set (OS HR 2.74, P < 0.001; PFS HR 1.61, P = 0.014). These findings were further validated in the internal validation set (OS HR 1.84, P = 0.015; PFS HR 1.58, P = 0.027) and again in the CGGA external validation set (OS HR 1.72, P = 0.001). Association between GRS and outcomes was observed only among patients who received RT (RT alone or CRT), in both TCGA and CGGA. Conclusions: This study successfully identified an expression signature of five genes that stratified outcomes among LGG patients who received adjuvant RT, with two rounds of validation leveraging independent genomics databases. Expression levels of the highlighted genes were associated with survival only among patients whose treatments included RT, but not among those with omission of RT, suggesting that expression of these genes may be predictive of radiation treatment response. While additional prospective studies are warranted, interrogation of these genes to determine high/low GRS may be considered in the multidisciplinary management of LGGs.

scholarly journals KRAS pathway expression changes in pancreatic cancer models by conventional and experimental taxanes

Mutagenesis ◽  
2019 ◽  
Vol 34 (5-6) ◽  
pp. 403-411
Author(s):  
M Oliverius ◽  
D Flasarova ◽  
B Mohelnikova-Duchonova ◽  
M Ehrlichova ◽  
V Hlavac ◽  
...  
Keyword(s):  
Gene Expression ◽  
Kras Mutation ◽  
Expression Profiles ◽  
Signalling Pathway ◽  
Wild Type ◽  
Mutation Status ◽  
Pathway Expression ◽  
Kras Mutation Status

Abstract The KRAS signalling pathway is pivotal for pancreatic ductal adenocarcinoma (PDAC) development. After the failure of most conventional cytotoxic and targeted therapeutics tested so far, the combination of taxane nab-paclitaxel (Abraxane) with gemcitabine recently demonstrated promising improvements in the survival of PDAC patients. This study aimed to explore interactions of conventional paclitaxel and experimental taxane SB-T-1216 with the KRAS signalling pathway expression in in vivo and in vitro PDAC models in order to decipher potential predictive biomarkers or targets for future individualised therapy. Mouse PDAC PaCa-44 xenograft model was used for evaluation of changes in transcript and protein levels of the KRAS signalling pathway caused by administration of experimental taxane SB-T-1216 in vivo. Subsequently, KRAS wild-type (BxPc-3) and mutated (MiaPaCa-2 and PaCa-44) cell line models were treated with paclitaxel to verify dysregulation of the KRAS signalling pathway gene expression profile in vitro and investigate the role of KRAS mutation status. By comparing the gene expression profiles, this study observed for the first time that in vitro cell models differ in the basal transcriptional profile of the KRAS signalling pathway, but there were no differences between KRAS mutated and wild-type cells in sensitivity to taxanes. Generally, the taxane administration caused a downregulation of the KRAS signalling pathway both in vitro and in vivo, but this effect was not dependent on the KRAS mutation status. In conclusion, putative biomarkers for prediction of taxane activity or targets for stimulation of taxane anticancer effects were not discovered by the KRAS signalling pathway profiling in various PDAC models.

Abstract 130: Hypercholesterolemia Suppresses Carotid Artery Endothelial NOS3 Expression via Epigenetic Mechanisms

2015 ◽  
Vol 35 (suppl_1) ◽  
Author(s):  
Alex Sotolongo ◽  
Yi-Zhou Jiang ◽  
John Karanian ◽  
William Pritchard ◽  
Peter Davies
Keyword(s):  
Gene Expression ◽  
Dna Methylation ◽  
Endothelial Cells ◽  
Dna Methyltransferase ◽  
Control Group ◽  
High Cholesterol Diet ◽  
Cholesterol Diet ◽  
High Cholesterol ◽  
High Fat

Objective: One of the first clinically detectable changes in the vasculature during atherogenesis is the accumulation of cholesterol within the vessel wall. Hypercholesterolemia is characterized by dysfunctional endothelial-dependent vessel relaxation and impaired NOS3 function. Since DNA methylation at gene promoter regions strongly suppresses gene expression, we postulated that high-fat/high-cholesterol diet suppresses endothelial NOS3 through promoter DNA methylation. Methods: Domestic male pigs were fed control diet (CD) or isocaloric high fat and high cholesterol diet (HC; 12% fat and 1.5% cholesterol) for 2, 4, 8 or 12 weeks prior to tissue collection. Furthermore, to determine the effects of risk factor withdrawal, an additional group of swine received HC for 12 weeks and then CD for 8 weeks; a control group received HC continuously for 20 weeks. Endothelial cells were harvested from common carotid aorta. In parallel in vitro studies, cultured human aortic endothelial cells (HAEC) were treated with human LDL, GW3956 (LXR agonist) and RG108 (DNA methyltransferase [DNMT] inhibitor). In cells from both sources, DNA methylation at the NOS3 promoter was measured using methylation specific pyro sequencing, and endothelial gene expression was measured using RT PCR. Results: HC diet increased plasma cholesterol level from 75 mg/dl on CD to a plateau of about 540 mg/dl within 2 weeks. Endothelial NOS3 expression was significantly reduced (71±9 % of CD) after 4 weeks of HC, a level sustained at subsequent time points. Withdrawal of HC for 8 weeks did not recover NOS3 expression. After 12-week HC, the NOS3 promoter was hypermethylated. Withdrawal of HC did not reverse NOS3 promoter methylation. In vitro treatment of HAEC with human LDL (200 mg/dl total cholesterol) or GW3956 (5μM) suppressed NOS3 mRNA to 50% and 30% respectively, suggesting that LXR/RXR is involved in suppression of NOS3. Nitric oxide production was consistently suppressed by GW3959. Both could be reversed through inhibition of DNMTs by RG108. Conclusions: DNA methylation and LXR/RXR pathway can mediate the HC-suppression of endothelial NOS3. The study identifies novel pharmaceutical targets in treating endothelial dysfunction. Crosstalk between these pathways is under investigation.

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