scholarly journals Engrailed 1 overexpression as a potential prognostic marker in Lower Grade Glioma

PeerJ ◽  
2019 ◽  
Vol 7 ◽  
pp. e7414
Author(s):  
Jin Zhu ◽  
Yu-Qi Zhang
Keyword(s):  
Survival Time ◽  
Prognostic Marker ◽  
Cox Regression ◽  
Bioinformatic Analysis ◽  
Idh1 Mutation ◽  
The Cancer Genome Atlas ◽  
Lower Grade ◽  
Mutation Status ◽  
Lower Grade Glioma ◽  
Cancer Types

Background Engrailed 1 (EN1), as a member of homeobox-containing transcription factors, participates in the development of the brain. High expressions of EN1 exist in various tumors. However, the role of EN1 in lower grade glioma (LGG) is still unknown. Methods Coefficients of Cox regression were examined by data mining among 13 cancer types using OncoLnc to validate EN1 expressions in LGG patients from The Cancer Genome Atlas database (TCGA). Bioinformatic analysis was performed by using R2 and the UCSC Xena browser based on the data from 273 glioma cases in GSE16011 from GEO datasets and 530 cases of LGG patients in TCGA. Cases in GSE16011 were divided into two groups according to IDH1 mutation status. Cases in TCGA-LGG were classified to subtypes according to histopathological results, IDH1 mutation status and 1p19q status. The Kaplan–Meier survival curves were performed to analyze the relationship between EN1 expressions and clinicopathological characteristics and survival time respectively. Results Cox regression results showed that LGG was ranked statistically first among 13 different cancer types according to the false discovery rate (FDR) correction. Results from GSE16011 showed that: glioma, LGG and LGG with IDH1 mutation patients with high EN1 expressions had significantly shorter 5, 10, and 15-year overall survival time (OS) (p < 0.001). Similar results from TCGA-LGG showed that LGG patients with high EN1 expressions had significantly shorter 15-year OS, irrespective of IDH1 mutation and 1p19q co-deletion (p < 0.001). The astrocytoma subgroup showed highest levels of EN1 expression and shortest 5, 10 and 15-year OS compared with oligoastrocytoma and oligodendroglioma (p < 0.05). Conclusion EN1 can be used as a prognostic marker in LGG patients, combined with IDH1 mutation and 1p19q co-deletion.

scholarly journals Identification and Validation of an Energy Metabolism-Related lncRNA-mRNA Signature for Lower-Grade Glioma

2020 ◽  
Vol 2020 ◽  
pp. 1-14
Author(s):  
Jingwei Zhao ◽  
Le Wang ◽  
Bo Wei
Keyword(s):  
Energy Metabolism ◽  
Risk Score ◽  
Cox Regression ◽  
The Cancer Genome Atlas ◽  
Coexpression Network ◽  
Normal Brain ◽  
Lower Grade ◽  
Prognostic Signature ◽  
Lower Grade Glioma ◽  
Genome Atlas

Energy metabolic processes play important roles for tumor malignancy, indicating that related protein-coding genes and regulatory upstream genes (such as long noncoding RNAs (lncRNAs)) may represent potential biomarkers for prognostic prediction. This study will develop a new energy metabolism-related lncRNA-mRNA prognostic signature for lower-grade glioma (LGG) patients. A GSE4290 dataset obtained from Gene Expression Omnibus was used for screening the differentially expressed genes (DEGs) and lncRNAs (DELs). The Cancer Genome Atlas (TCGA) dataset was used as the prognosis training set, while the Chinese Glioma Genome Atlas (CGGA) was for the validation set. Energy metabolism-related genes were collected from the Molecular Signatures Database (MsigDB), and a coexpression network was established between energy metabolism-related DEGs and DELs to identify energy metabolism-related DELs. Least absolute shrinkage and selection operator (LASSO) analysis was performed to filter the prognostic signature which underwent survival analysis and nomogram construction. A total of 1613 DEGs and 37 DELs were identified between LGG and normal brain tissues. One hundred and ten DEGs were overlapped with energy metabolism-related genes. Twenty-seven DELs could coexpress with 67 metabolism-related DEGs. LASSO regression analysis showed that 9 genes in the coexpression network were the optimal signature and used to construct the risk score. Kaplan-Meier curve analysis showed that patients with a high risk score had significantly worse OS than those with a low risk score (TCGA: HR=3.192, 95%CI=2.182‐4.670; CGGA: HR=1.922, 95%CI=1.431‐2.583). The predictive accuracy of the risk score was also high according to the AUC of the ROC curve (TCGA: 0.827; CGGA: 0.806). Multivariate Cox regression analyses revealed age, IDH1 mutation, and risk score as independent prognostic factors, and thus, a prognostic nomogram was established based on these three variables. The excellent prognostic performance of the nomogram was confirmed by calibration and discrimination analyses. In conclusion, our findings provided a new biomarker for the stratification of LGG patients with poor prognosis.

scholarly journals Fractal analysis of 11C-methionine PET in patients with newly diagnosed glioma

2021 ◽  
Vol 8 (1) ◽  
Author(s):  
Yukito Maeda ◽  
Yuka Yamamoto ◽  
Takashi Norikane ◽  
Katsuya Mitamura ◽  
Tetsuhiro Hatakeyama ◽  
...  
Keyword(s):  
Fractal Dimension ◽  
Fractal Analysis ◽  
Anaplastic Astrocytoma ◽  
Idh1 Mutation ◽  
Lower Grade ◽  
Diffuse Astrocytoma ◽  
Newly Diagnosed ◽  
Mutation Status ◽  
Lower Grade Glioma ◽  
Met Pet

Abstract Background The present study tested the possible utility of fractal analysis from l-[methyl-11C]-methionine (MET) uptake in patients with newly diagnosed gliomas for differentiating glioma, especially in relation to isocitrate dehydrogenase 1 (IDH1) mutation status, and as compared with the conventional standardized uptake value (SUV) parameters. Methods Investigations of MET PET/CT were performed retrospectively in 47 patients with newly diagnosed glioma. Tumors were divided into three groups: lower grade glioma (IDH1-mutant diffuse astrocytoma and IDH1-mutant anaplastic astrocytoma), higher grade glioma (IDH1-wildtype diffuse astrocytoma and IDH1-wildtype anaplastic astrocytoma), and glioblastoma. The fractal dimension for tumor, maximum SUV (SUVmax) for tumor (T) and mean SUV for normal contralateral hemisphere (N) were calculated, and the tumor-to-normal (T/N) ratio was determined. Metabolic tumor volume (MTV) and total lesion MET uptake (TLMU) were also measured. Results There were significant differences in SUVmax (p = 0.006) and T/N ratio (p = 0.02) between lower grade glioma and glioblastoma. There were no significant differences among any of the three groups in MTV or TLMU. Significant differences were obtained in the fractal dimension between lower grade glioma and higher grade glioma (p = 0.006) and glioblastoma (p < 0.001). Conclusions The results of this preliminary study in a small patient population suggest that the fractal dimension using MET PET in patients with newly diagnosed gliomas is useful for differentiating glioma, especially in relation to IDH1 mutation status, which has not been possible with SUV parameters.

scholarly journals MOMC-3. Hypermethylation and overexpression of HOX genes are poor prognosticators in Lower-Grade Glioma

2021 ◽  
Vol 3 (Supplement_2) ◽  
pp. ii4-ii4
Author(s):  
Yasin Mamatjan ◽  
Mathew Voisin ◽  
Farshad Nassiri ◽  
Fabio Moraes ◽  
Severa Bunda ◽  
...  
Keyword(s):  
Hox Genes ◽  
Cox Regression ◽  
The Cancer Genome Atlas ◽  
P Value ◽  
Low Grade ◽  
Lower Grade ◽  
Cox Regression Analysis ◽  
Hox Gene ◽  
Lower Grade Glioma ◽  
Diffuse Gliomas

Abstract Diffuse gliomas represent over 80% of malignant brain tumors ranging from low-grade to aggressive high-grade lesions. Molecular characterization of these tumors led to the development of new classification system comprising specific glioma subtypes. While this provides novel molecular insight into gliomas it does not fully explain the variability in patient outcome. To identify and characterize a predictive signature of outcome in diffuse gliomas, we utilized an integrative molecular analysis (methylation, mRNA, copy number variation (CNV) and mutation data) using multiple molecular platforms, including a total of 310 IDH mutant glioma samples from University Health Network (UHN) and German Cancer Research Center (DKFZ) together with 419 samples from The Cancer Genome Atlas (TCGA). Cox regression analysis of methylation data from the UHN cohort identified CpG-based signatures that split the glioma cohort into two prognostic groups strongly predicting survival (p-value &lt; 0.0001). The CpG-based signatures were reliably validated using two independent datasets from TCGA and DKFZ cohorts (both p-values &lt; 0.0001). The results show that the methylation signatures that predict poor outcome also correlated with G-CIMP low status, elevated CNV instability and hypermethylation of a set of HOX gene probes. Further study in diffuse lower-grade glioma (LGG) using integrated mRNA and methylation (iRM) analyses showed that parallel HOX gene overexpression and hypermethylation in the same direction were significantly associated with increased mutational load, high aneuploidy and worse survival (p-value &lt; 0.0001). Furthermore, this iRM high group was characterized by a 7-HOX gene signature showed significant survival differences not only in IDH mutant LGG but also in IDH wildtype LGG. These results demonstrate the importance of HOX genes in predicting the outcome of diffuse gliomas to identify relevant molecular subtyping independent of histology.

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.

The Role of Surgery in IDH-Wild-Type Lower-Grade Gliomas: Threshold at a High Extent of Resection Should be Pursued

Neurosurgery ◽  
2021 ◽  
Author(s):  
Peng Wang ◽  
Chen Luo ◽  
Peng-jie Hong ◽  
Wen-ting Rui ◽  
Shuai Wu
Keyword(s):  
Cox Regression ◽  
Progression Free Survival ◽  
Extent Of Resection ◽  
Lower Grade ◽  
Wild Type ◽  
Cox Regression Analysis ◽  
Kaplan Meier ◽  
Lower Grade Glioma ◽  
Clinical Benefits

Abstract BACKGROUND While maximizing extent of resection (EOR) is associated with longer survival in lower-grade glioma (LGG) patients, the number of cases remains insufficient in determining a EOR threshold to elucidate the clinical benefits, especially in IDH-wild-type LGG patients. OBJECTIVE To identify the effects of EOR on the survival outcomes of IDH-wild-type LGG patients. METHODS IDH-wild-type LGG patients were retrospectively reviewed. The effect of EOR and other predictor variables on overall survival (OS) and progression-free survival (PFS) was analyzed using Cox regression models and the Kaplan-Meier method. RESULTS A total of 94 patients (median OS: 48.9 mo; median follow-up: 30.6 mo) were included in this study. In the multivariable Cox regression analysis, postoperative residual volume was associated with prolonged OS (HR = 2.238; 95% confidence interval [CI], 1.130-4.435; P = .021) and PFS (HR = 2.075; 95% CI, 1.113-3.869; P = .022). Thresholds at a minimum EOR of 97.0% or a maximum residue of 3.0 cm3 were necessary to impact OS positively. For the telomerase reverse transcriptase (TERT)p-wild-type group, such an association was absent. Significant differences in survival existed between the TERTp-wild-type and mutant patients who underwent relatively incomplete resections (residual ≥2.0 cm3 + TERTp wild type: median OS of 62.6 mo [95% CI: 39.7-85.5 mo]; residual ≥2.0 cm3 + TERTp mutant: median OS of 20.0 mo [95% CI:14.6-25.4 mo]). CONCLUSION Our results support the core role of maximal safe resection in the treatment of IDH-wild-type LGGs, especially for IDH-wild-type + TERTp-mutant LGGs. Importantly, the survival benefits of surgery could only be elucidated at a high EOR cut-off point.

scholarly journals A comprehensive analysis of the angiogenesis-related genes in glioblastoma multiforme vs. brain lower grade glioma

2020 ◽  
Vol 78 (1) ◽  
pp. 34-38
Author(s):  
Burcu BITERGE-SUT
Keyword(s):  
Glioblastoma Multiforme ◽  
Malignant Gliomas ◽  
Genetic Alterations ◽  
Cancer Genome ◽  
The Cancer Genome Atlas ◽  
Lower Grade ◽  
Nonsense Mutations ◽  
Lower Grade Glioma ◽  
Cancer Genome Atlas ◽  
Genome Atlas

Abstract Brain tumors are one of the most common causes of cancer-related deaths around the world. Angiogenesis is critical in high-grade malignant gliomas, such as glioblastoma multiforme. Objective: The aim of this study is to comparatively analyze the angiogenesis-related genes, namely VEGFA, VEGFB, KDR, CXCL8, CXCR1 and CXCR2 in LGG vs. GBM to identify molecular distinctions using datasets available on The Cancer Genome Atlas (TCGA). Methods: DNA sequencing and mRNA expression data for 514 brain lower grade glioma (LGG) and 592 glioblastoma multiforme (GBM) patients were acquired from The Cancer Genome Atlas (TCGA), and the genetic alterations and expression levels of the selected genes were analyzed. Results: We identified six distinct KDR mutations in the LGG patients and 18 distinct KDR mutations in the GBM patients, including missense and nonsense mutations, frame shift deletion and altered splice region. Furthermore, VEGFA and CXCL8 were significantly overexpressed within GBM patients. Conclusions: VEGFA and CXCL8 are important factors for angiogenesis, which are suggested to have significant roles during tumorigenesis. Our results provide further evidence that VEGFA and CXCL8 could induce angiogenesis and promote LGG to progress into GBM. These findings could be useful in developing novel targeted therapeutics approaches in the future.

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 Heme Oxygenase-1 Predicts Risk Stratification and Immunotherapy Efficacy in Lower Grade Gliomas

2021 ◽  
Vol 9 ◽  
Author(s):  
Wenrui Ye ◽  
Zhixiong Liu ◽  
Fangkun Liu ◽  
Cong Luo
Keyword(s):  
Single Cell ◽  
Heme Oxygenase ◽  
Clinical Decision Making ◽  
Cox Regression ◽  
Risk Group ◽  
Heme Oxygenase 1 ◽  
Lower Grade ◽  
Sequencing Data ◽  
Lower Grade Glioma ◽  
Functional States

Background: Gliomas are the most common tumors in human brains with unpleasing outcomes. Heme oxygenase-1 (HMOX1, HO-1) was a potential target for human cancers. However, their relationship remains incompletely discussed.Methods: We employed a total of 952 lower grade glioma (LGG) patients from TCGA and CGGA databases, and 29 samples in our hospital for subsequent analyses. Expression, mutational, survival, and immune profiles of HMOX1 were comprehensively evaluated. We constructed a risk signature using the LASSO Cox regression model, and further generated a nomogram model to predict survival of LGG patients. Single-cell transcriptomic sequencing data were also employed to investigated the role of HMOX1 in cancer cells.Results: We found that HMOX1 was overexpressed and was related to poorer survival in gliomas. HMOX1-related genes (HRGs) were involved in immune-related pathways. Patients in the high-risk group exhibited significantly poorer overall survival. The risk score was positively correlated with the abundance of resting memory CD4+ T cells, M1, M2 macrophages, and activated dendritic cells. Additionally, immunotherapy showed potent efficacy in low-risk group. And patients with lower HMOX1 expression were predicted to have better response to immunotherapies, suggesting that immunotherapies combined with HMOX1 inhibition may execute good responses. Moreover, significant correlations were found between HMOX1 expression and single-cell functional states including angiogenesis, hypoxia, and metastasis. Finally, we constructed a nomogram which could predict 1-, 3-, and 5-year survival in LGG patients.Conclusion:HMOX1 is involved in immune infiltration and predicts poor survival in patients with lower grade glioma. Importantly, HMOX1 were related to oncological functional states including angiogenesis, hypoxia, and metastasis. A nomogram integrated with the risk signature was obtained to robustly predict glioma patient outcomes, with the potential to guide clinical decision-making.

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