The Clinical Significance and Transcription Regulation of a DNA Damage Repair Gene, SMC4, in Low-Grade Glioma via Integrated Bioinformatic Analysis.
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ABSTRACT:
SUBMITTER: Wang Y
PROVIDER: S-EPMC8636002 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Secondary glioblastoma (sGBM) is a type of glioblastoma multiforme that evolves from low-grade glioma (LGG). However, the mechanism of this transition still remains poorly understood. In this study, we used weighted gene co-expression network analysis (WGCNA) on the gene expression profiles of glioma samples from the Chinese Glioma Genome Atlas (CGGA) database to identify key genetic module related to distinguish histological characteristics. Here, the brown module was highly correlated with histological characteristics and was selected as the hub module. By applying functional annotation analysis, we found that biological processes related to the cell-cycle and DNA-replication were enriched in the genes of the brown module. After constructing a protein-protein interaction (PPI) network, validation of differential gene expression, and survival analyses, we ultimately identified five hub genes: CCNB2 (Cyclin B2), KIF2C (Kinesin Family Member 2C), CDC20 (Cell Division Cycle 20), TPX2 (TPX2 Microtubule Nucleation Factor), and PLK1 (Polo Like Kinase 1). In addition, a computational risk model was developed for predicting the clinical outcomes of sGBM patients by combining gene expression levels. This gene signature was demonstrated to be an independent predictor of survival by univariate and multivariable Cox regression analysis. Finally, we used the Genomics of Drug Sensitivity in Cancer (GDSC) database to predict the responses of sGBM patients to routine chemotherapeutic drugs. Patients from the high-risk group were more sensitive to common chemotherapies during clinical treatment. Our findings based on comprehensive analyses might advance the understanding of sGBM transition and aid the development of novel biomarkers for diagnosing and predicting the survival of sGBM patients.
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Project description:To examine the effect of Nf1 inactivation in astrocytes on normal microglia in the optic nerve, microglia from Nf1 flox/flox (FF) and Nf1 flox/flox; GFAP-Cre (FFC) were flow sorted. High throughput RNA-seq was employed to compare the expression profiles, and upregulated genes in microglia supportive to Nf1 deficient astrocytes were verified.
2020-07-03 | GSE65865 | GEO
Project description:IntroductionGlioma is the most common primary tumor in the brain.Integrin beta 2(ITGB2) is a member of the leukocyte integrin family (leukocyte integrin), participating in lymphocyte recycling and homing, cell adhesion, and cell surface-mediated signal transduction. However, few studies on ITGB2 in gliomas have been reported yet.This study first discussed the relationship between ITGB2 expression and clinical characterization of glioma and the prognostic significance of its methylation in low-grade glioma.MethodsWe collected Clinical data and transcription of glioma patients from TCGA, CGGA, and Rembrant datasets to analyze the differential expression of ITGB2 mRNA in glioma tissues and normal tissues. The box polts to evaluated the expression patterns of ITGB2 in different molecular subtypes. Receiver operating characteristic curve (ROC) were used to evaluate and verify the reliability of the model. Kaplan-Meier survival curves to evaluated the relationship between the level of ITGB2 mRNA expression and overall survival (OS). Using cox regression analysis to verify the ability of ITGB2 as an independent predictor of OS in glioma patients. We use TIMER to analyze and visualize the association between immune infiltration levels and a range of variables. The methylation of GBMLGG patients were obtained from the TCGA database through the biological portal.ResultsITGB2 can be a potential marker for mesenchymal molecular subtype gliomas. COX regression analysis shows that ITGB2 is an independent predictive marker of OS in malignant glioma patients. Biological processes show that ITGB2 has involved glioma immune-related activities, especially closely related to B cells, CD4+Tcells, macrophages, neutrophils, and dendritic cells. ITGB2 is negatively regulated by ITGB2 methylation, resulting in low expression in LGG tissues. Low expression of ITGB2 and high methylation indicate good OS in patients with LGG. The ITGB2 methylation risk score (ITMRS) obtained from the ITGB2 methylation CpG site can better predict the OS of LGG patients. We used univariate and multivariate cox regression analysis of methylationsites, used the R language predict function to obtain the risk score of these ITGB2 methylation sites(ITMRS).DiscussionITGB2 can be used as a potential marker of mesenchymal molecular subtypes of gliomas and as an independent predictive marker of OS in patients with malignant gliomas. The ITMRS we established can be used as an independent prognostic factor for LGG and provide a new idea for the diagnosis and treatment of LGG.
| S-EPMC9880157 | biostudies-literature
Project description:Purpose of reviewPediatric low-grade gliomas (pLGGs) have been treated with similar therapies for the last 30 years. Recent biological insights have allowed a new generation of targeted therapies to be developed for these diverse tumors. At the same time, technological advances may redefine the late toxicities associated with radiation therapy. Understanding recent developments in pLGG therapy is essential to the management of these common pediatric tumors.Recent findingsIt is now well understood that aberrations of the mitogen-activated protein kinase pathway are key to oncogenesis in low-grade gliomas. This understanding, along with the development of available targeted agents, have heralded a new era of understanding and treatment for these patients. Promising, sustained responses are now being seen in early phase trials among patients with multiply recurrent/progressive disease. Also, newer and highly conformal radiation approaches such as proton beam radiotherapy maintain efficacy of radiation but limit radiation-associated toxicities.SummaryNovel therapies offer the potential for tumor control with greatly reduced toxicities. However, late effects of these therapies are just now being explored. Improved radiation approaches and targeted agents have the potential to redefine traditional therapy for pLGG.
| S-EPMC6664811 | biostudies-literature
Project description:Samples of resected tumor from patients with low- and high-grade gliomas
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Project description:Although radiotherapy is a well-known effective non-surgical treatment for malignant gliomas, the therapeutic efficacy is severely limited due to the radioresistance of tumor cells. Previously, we demonstrated that Yes-associated protein (YAP) promotes glioma malignant progression. However, whether YAP plays a role in radioresistance and its potential value in cancer treatment are still unclear. In this study, we found that high YAP expression is associated with poor prognosis in malignant glioma patients undergoing radiotherapy. Research in immortalized cell lines and primary cells from GBM patients revealed that YAP exhibited a radioresistant effect on gliomas via promoting DNA damage repair. Mechanistically, after radiation, YAP was translocated into the nucleus, where it promoted the expression and secretion of FGF2, leading to MAPK-ERK pathway activation. FGF2 is a novel target gene of YAP. Inhibition of YAP-FGF2-MAPK signaling sensitizes gliomas to radiotherapy and prolongs the survival of intracranial cell-derived and patient-derived xenograft models. These results suggest that YAP-FGF2-MAPK is a key mechanism of radioresistance and is an actionable target for improving radiotherapy efficacy.
| S-EPMC8266683 | biostudies-literature
Project description:BackgroundLarge-scale genome-wide association studies (GWAS) have implicated thousands of germline genetic variants in modulating individuals' risk to various diseases, including cancer. At least 25 risk loci have been identified for low-grade gliomas (LGGs), but their molecular functions remain largely unknown.MethodsWe hypothesized that GWAS loci contain causal single nucleotide polymorphisms (SNPs) that reside in accessible open chromatin regions and modulate the expression of target genes by perturbing the binding affinity of transcription factors (TFs). We performed an integrative analysis of genomic and epigenomic data from The Cancer Genome Atlas and other public repositories to identify candidate causal SNPs within linkage disequilibrium blocks of LGG GWAS loci. We assessed their potential regulatory role via in silico TF binding sequence perturbations, convolutional neural network trained on TF binding data, and simulated annealing-based interpretation methods.ResultsWe built an interactive website (http://education.knoweng.org/alg3/) summarizing the functional footprinting of 280 variants in 25 LGG GWAS regions, providing rich information for further computational and experimental scrutiny. We identified as case studies PHLDB1 and SLC25A26 as candidate target genes of rs12803321 and rs11706832, respectively, and predicted the GWAS variant rs648044 to be the causal SNP modulating ZBTB16, a known tumor suppressor in multiple cancers. We showed that rs648044 likely perturbed the binding affinity of the TF MAFF, as supported by RNA interference and in vitro MAFF binding experiments.ConclusionsThe identified candidate (causal SNP, target gene, TF) triplets and the accompanying resource will help accelerate our understanding of the molecular mechanisms underlying genetic risk factors for gliomas.
| S-EPMC8041333 | biostudies-literature
Project description:BackgroundHigh-grade gliomas (HGGs) exhibit marked heterogeneity in clinical behavior. The purpose of this study was to identify a novel biomarker that predicts patient outcome, which is helpful in HGG patient management.MethodsWe analyzed gene expression profiles of 833 HGG cases, representing the largest patient population ever reported. Using the data set from the Cancer Genome Atlas (TCGA) and random partitioning approach, we performed Cox proportional hazards model analysis to identify novel prognostic mRNAs in HGG. The predictive capability was further assessed via multivariate analysis and validated in 4 additional data sets. The Kaplan-Meier method was used to evaluate survival difference between dichotomic groups of patients. Correlation of gene expression and DNA methylation was evaluated via Student's t-test.ResultsPatients with elevated FBXO17 expression had a significantly shorter overall survival (OS) (P?=?0.0011). After adjustment by IDH1 mutation, sex, and patient age, FBXO17 gene expression was significantly associated with OS (HR?=?1.29, 95% CI =1.04-1.59, P?=?0.018). In addition, FBXO17 expression can significantly distinguish patients by OS not only among patients who received temozolomide chemotherapy (HR 1.35, 95% CI =1.12-1.64, P?=?0.002) but also among those who did not (HR?=?1.48, 95% CI =1.20-1.82, P?<?0.0001). The significant association of FBXO17 gene expression with OS was further validated in four external data sets. We further found that FBXO17 endogenous expression is significantly contributable from its promoter methylation.ConclusionEpigenetically modulated FBXO17 has a potential as a stratification factor for clinical decision-making in HGG.
| S-EPMC6069786 | biostudies-literature
Project description:Background:Extensive resections in low-grade glioma (LGG) are associated with improved overall survival (OS). However, World Health Organization (WHO) classification of gliomas has been completely revised and is now predominantly based on molecular criteria. This requires reevaluation of the impact of surgery in molecularly defined LGG subtypes. Methods:We included 228 adults who underwent surgery since 2003 for a supratentorial LGG. Pre- and postoperative tumor volumes were assessed with semiautomatic software on T2-weighted images. Targeted next-generation sequencing was used to classify samples according to current WHO classification. Impact of postoperative volume on OS, corrected for molecular profile, was assessed using a Cox proportional hazards model. Results:Median follow-up was 5.79 years. In 39 (17.1%) histopathologically classified gliomas, the subtype was revised after molecular analysis. Complete resection was achieved in 35 patients (15.4%), and in 54 patients (23.7%) only small residue (0.1-5.0 cm3) remained. In multivariable analysis, postoperative volume was associated with OS, with a hazard ratio of 1.01 (95% CI: 1.002-1.02; P = 0.016) per cm3 increase in volume. The impact of postoperative volume was particularly strong in isocitrate dehydrogenase (IDH) mutated astrocytoma patients, where even very small postoperative volumes (0.1-5.0 cm) already negatively affected OS. Conclusion:Our data provide the necessary reevaluation of the impact of surgery in molecularly defined LGG and support maximal resection as first-line treatment for molecularly defined LGG. Importantly, in IDH mutated astrocytoma, even small postoperative volumes have negative impact on OS, which argues for a second-look operation in this subtype to remove minor residues if safely possible.
| S-EPMC5761503 | biostudies-other
Project description:Low-grade glioma (LGG) is the most common brain tumor in children and has excellent long-term survival. With an excellent survival rate, the choice of treatment involves careful consideration of minimizing late toxicity from surgery, radiation, and chemotherapy. Surgery, radiation therapy, and chemotherapy can be used as monotherapy or in combination, providing different therapeutic ratios and complications. As a result, establishing the selection of ideal therapies has been a controversial area, presenting challenges. Recent advances in understanding molecular characteristics of pediatric LGG affect classification and treatment approaches. This review aims to overview recent developments in medical treatment in pediatric LGG.
| S-EPMC9650116 | biostudies-literature