Dataset Information

Novel immune checkpoint-related gene model to predict prognosis and treatment responsiveness in low-grade gliomas.

ABSTRACT: Recently, studies have shown that immune checkpoint-related genes (ICGs) are instrumental in maintaining immune homeostasis and can be regarded as potential therapeutic targets. However, the prognostic applications of ICGs require further elucidation in low-grade glioma (LGG) cases. In the present study, a unique prognostic gene signature in LGG has been identified and validated as well based on ICGs as a means of facilitating clinical decision-making. The RNA-seq data as well as corresponding clinical data of LGG samples have been retrieved utilizing the Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. ICG-defined non-negative matrix factorization (NMF) clustering was performed to categorize patients with LGG into two molecular subtypes with different prognoses, clinical traits, and immune microenvironments. In the TCGA database, a signature integrating 8 genes has been developed utilizing the LASSO Cox method and validated in the GEO database. The signature developed is superior to other well-recognized signatures in terms of predicting the survival probability of patients with LGG. This 8-gene signature was then subsequently applied to categorize patients into high- and low-risk groups, and differences between them in terms of gene alteration frequency were observed. There were remarkable variations in IDH1 (91% and 64%) across low-as well as high-risk groups. Additionally, various analyses like function enrichment, tumor immune microenvironment, and chemotherapy drug sensitivity revealed significant variations across high- and low-risk populations. Overall, this 8-gene signature may function as a useful tool for prognosis and immunotherapy outcome predictions among LGG patients.

SUBMITTER: Guo Y

PROVIDER: S-EPMC10559968 | biostudies-literature | 2023 Sep

REPOSITORIES: biostudies-literature

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Novel immune checkpoint-related gene model to predict prognosis and treatment responsiveness in low-grade gliomas.

Guo Yangyang Y Bao Jingxia J Lin Danfeng D Hong Kai K Cen Kenan K Sun Jie J Wang Zhepei Z Wu Zhixuan Z

Heliyon 20230914 9

Recently, studies have shown that immune checkpoint-related genes (ICGs) are instrumental in maintaining immune homeostasis and can be regarded as potential therapeutic targets. However, the prognostic applications of ICGs require further elucidation in low-grade glioma (LGG) cases. In the present study, a unique prognostic gene signature in LGG has been identified and validated as well based on ICGs as a means of facilitating clinical decision-making. The RNA-seq data as well as corresponding c ...[more]

PMID: 37809899

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Project description:BackgroundAbnormalities in centrosome regulatory genes can induce chromosome instability, cell differentiation errors, and tumorigenesis. However, a limited number of comprehensive analyses of centrosome-related genes have been performed in low-grade gliomas (LGG).MethodsLGG data were extracted from The Cancer Genome Atlas (TCGA) and Chinese Glioma Genome Atlas (CGGA) databases. The ConsensusClusterPlus" R package was used for unsupervised clustering. We constructed a centrosome-related genes (CRGs) signature using a random forest model, lasso Cox model, and multivariate Cox model, and quantified the centrosome-related risk score (centS). The prognostic prediction efficacy of centS was evaluated using a Receiver Operating Characteristic (ROC) curve. Immune cell infiltration and genomic mutational landscapes were evaluated using the ESTIMATE algorithm, single-sample Gene Set Enrichment Analysis (ssGSEA) algorithm, and "maftools" R package, respectively. Differences in clinical features, isocitrate dehydrogenase (IDH) mutation, 1p19q codeletion, O6-methylguanine-DNA methyltransferase promoter (MGMTp) methylation, and response to antitumor therapy between the high- and low-centS groups were explored. "pRRophetic" R packages were used for temozolomide (TMZ) sensitivity analysis. qRT-PCR verified the differential expression of the centrosomal gene team, the core of which is CEP135, between LGG cells and normal cells.ResultsTwo distinct CRG-based clusters were identified using consensus unsupervised clustering analysis. The prognosis, biological characteristics, and immune cell infiltration of the two clusters differed significantly. A well-performing centS signature was developed to predict the prognosis of patients with LGG based on 12 potential CRGs. We found that patients in the high-centS group showed poorer prognosis and lower proportion of IDH mutation and 1p19q codeletion compared to those in the low-centS group. Furthermore, patients in the high-centS group showed higher sensitivity to TMZ, higher tumor mutation burden, and immune cell infiltration. Finally, we identified a centrosomal gene team whose core was CEP135, and verified their differential expression between LGG cells and normal glial cells.ConclusionOur findings reveal a novel centrosome-related signature for predicting the prognosis and therapeutic responsiveness of patients with LGG. This may be helpful for the accurate clinical treatment of LGG.

Project description:BackgroundImmune checkpoint blockade (ICB) and anti-angiogenic drug combination has prolonged the survival of patients with advanced renal cell carcinoma (RCC). However, not all patients receive clinical benefits from this intervention. In this study, we aimed to establish a promising immune-related prognostic model to stratify the patients responding to ICB and anti-angiogenic drug combination and facilitate the development of personalized therapies for patients with RCC.Materials and methodsBased on clinical annotations and RNA-sequencing (RNA-seq) data of 407 patients with advanced RCC from the IMmotion151 cohort, nine immune-associated differentially expressed genes (DEGs) between responders and non-responders to atezolizumab (anti-programmed death-ligand 1 antibody) plus bevacizumab (anti-vascular endothelial growth factor antibody) treatment were identified via weighted gene co-expression network analysis. We also conducted single-sample gene set enrichment analysis to develop a novel immune-related risk score (IRS) model and further estimate the prognosis of patients with RCC by predicting their sensitivity to chemotherapy and responsiveness to immunotherapy. IRS model was further validated using the JAVELIN Renal 101 cohort, the E-MTAB-3218 cohort, the IMvigor210 and GSE78220 cohort. Predictive significance of the IRS model for advanced RCC was assessed using receiver operating characteristic curves.ResultsThe IRS model was constructed using nine immune-associated DEGs: SPINK5, SEMA3E, ROBO2, BMP5, ORM1, CRP, CTSE, PMCH and CCL3L1. Advanced RCC patients with high IRS had a high risk of undesirable clinical outcomes (hazard ratio = 1.91; 95% confidence interval = 1.43-2.55; P < 0.0001). Transcriptome analysis revealed that the IRS-low group exhibited significantly high expression levels of CD8+ T effectors, antigen-processing machinery, and immune checkpoints, whereas the epithelial-mesenchymal transition pathway was enriched in the IRS-high group. IRS model effectively differentiated the responders from non-responders to ICB combined with angiogenesis blockade therapy or immunotherapy alone, with area under the curve values of 0.822 in the IMmotion151 cohort, 0.751 in the JAVELIN Renal 101 cohort, and 0.776 in the E-MTAB-3218 cohort.ConclusionIRS model is a reliable and robust immune signature that can be used for patient selection to optimize the efficacy of ICB plus anti-angiogenic drug therapies in patients with advanced RCC.

Project description:BackgroundLow-grade glioma (LGG) is a common malignant tumor of the central nervous system. The clinical prognosis of different patients varies greatly, so exploring appropriate markers that affect the prognosis and treatment of LGG is important. The purpose of this study was to identify the potential effect of autophagy-related DNA methylation on the prognosis and immune microenvironment in LGG.MethodsThe methylation profile, transcription data and corresponding clinical information of 451 patients with LGG were obtained from The Cancer Genome Atlas (TCGA). Another methylation data and clinical information of 110 patients with LGG from Chinese Glioma Genome Atlas (CGGA) were used as the validation set. Through univariate and multivariate COX regression analysis, we identified the autophagy-related genes (ARGs) associated with methylation levels and prognosis, and established a risk assessment signature. The receiver operating characteristic (ROC) and Kaplan-Meier (KM) survival curve were used to verify the model's effectiveness in predicting prognosis. Patients were divided into low- and high-risk groups based on risk scores. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis were used to explore the differences in biological functions between the two groups. ESTIMATE and CIBERSORT algorithms were used to explore differences in immune infiltration and immunotherapy sites. Pearson correlation analysis was used to analyze the relative relationship between methylated cg sites and corresponding genes.ResultsA total of 6 ARGs (ARSB, CFLAR, WIPI2, RB1, ERN1, RAB24) were selected that were associated with methylation levels and prognosis. The area under the curve (AUC) =0.96, and the KM survival curve P<0.0001, which proves that the risk assessment model has a good effect in predicting the prognosis of LGG. GO and KEGG enrichment analysis showed that the model mainly involved major histocompatibility complex (MHC) II receptors, antigen processing and presentation, and immune cell differentiation. In addition, we also found differences in immune infiltration and immune checkpoints between high- and low-risk groups.ConclusionsThe methylation levels of these 6 ARGs have a strong predictive potential for LGG, and the methylation regulation of ARGs has an important impact on the immune microenvironment of LGGs.

Dataset Information

Novel immune checkpoint-related gene model to predict prognosis and treatment responsiveness in low-grade gliomas.

Publications

Novel immune checkpoint-related gene model to predict prognosis and treatment responsiveness in low-grade gliomas.

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