RNA processing genes characterize RNA splicing and further stratify lower-grade glioma

Chai, Rui‐Chao; Li, Yiming; Zhang, Kenan; Chang, Yuzhou; Liu, Yuqing; Zhao, Zheng; Wang, Zhiliang; Chang, Yuanhao; Li, Guanzhang; Wang, Kuanyu; Wu, Fan; Wang, Yongzhi

doi:10.1172/jci.insight.130591

Cited by 21 publications

(24 citation statements)

References 55 publications

(70 reference statements)

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“…Ultimately, a total of 41 OS-correlated genes, consisting of 34 risk associated genes and 7 protective genes, were selected to perform further gene signature selection and riskbased classification in the training dataset. A risk signature was formulated according to Least Absolute Shrinkage and Selection Operator (LASSO) regression algorithm (21)(22)(23)(24)(25). The penalty parameter λ was chosen based on a 50-fold cross validation within the training dataset, which produced the minimum mean cross-validated error for the Cox model.…”

Section: Discussionmentioning

confidence: 99%

Gene Expression Profiling Stratifies IDH-Wildtype Glioblastoma With Distinct Prognoses

Liu

et al. 2019

Front. Oncol.

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Objectives: In the present study, we aimed to determine the candidate genes that may function as biomarkers to further distinguish patients with isocitrate dehydrogenase (IDH)-wildtype glioblastoma (GBM), which are heterogeneous with respect to clinical outcomes. Materials and Methods: We selected 41 candidate genes associated with overall survival (OS) using univariate Cox regression from IDH-wildtype GBM patients based on RNA sequencing (RNAseq) expression data from the Chinese Glioma Genome Atlas (CGGA, n = 105) and The Cancer Genome Atlas (TCGA, n = 139) cohorts. Next, a sevengene-based risk signature was formulated according to Least Absolute Shrinkage and Selection Operator (LASSO) regression algorithm in the CGGA RNAseq database as a training set, while another 525 IDH-wildtype GBM patient TCGA datasets, consisting of RNA sequencing and microarray data, were used for validation. Patient survival in the low-and high-risk groups was calculated using Kaplan-Meier survival curve analysis and the log-rank test. Uni-and multivariate Cox regression analysis was used to assess the prognosis value. Gene oncology (GO) and gene set enrichment analysis (GSEA) were performed for the functional analysis of the seven-gene-based risk signature. Results: We developed a seven-gene-based signature, which allocated each patient to a risk group (low or high). Patients in the high-risk group had dramatically shorter overall survival than their low-risk counterparts in three independent cohorts. Univariate and multivariate analysis showed that the seven-gene signature remained an independent prognostic factor. Moreover, the seven-gene risk signature exhibited a striking prognostic validity, with AUC of 78.4 and 73.9%, which was higher than for traditional "age" (53.7%, 62.4%) and "GBM sub-type" (57.7%, 52.9%) in the CGGA-and TCGA-RNAseq databases, respectively. Subsequent bioinformatics analysis predicted that the sevengene signature was involved in the inflammatory response, immune response, cell adhesion, and apoptotic process. Conclusions: Our findings indicate that the seven-gene signature could be a potential prognostic biomarker. This study refined the current classification system of IDH-wildtype GBM and may provide a novel perspective for the research and individual therapy of IDH-wildtype GBM.

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Section: Discussionmentioning

confidence: 99%

Gene Expression Profiling Stratifies IDH-Wildtype Glioblastoma With Distinct Prognoses

Liu

et al. 2019

Front. Oncol.

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“…The IDH1 R132H, TERT promoter C228T and C250T, and BRAF V600E mutations were determined by pyrosequencing (PSQ) after PCR amplification in 66 cases where sufficient DNA could be extracted from FFPE samples (QIAmp DNA Mini Kit; Qiagen, Hilden, Germany); the PCR and sequencing primers used are listed in Supplementary Table 1. MGMT promoter methylation was also assessed by PSQ with the PyroMark Q24 MGMT kit on a PyroMarker Q24 instrument (Qiagen), as previously described [7]. Due to the limited DNA materials, we did not test the status of the non-canonical IDH mutations, such as non-IDH1 R132H and IDH2 mutations.…”

Section: Evaluation Of Histological and Molecular Pathological Featuresmentioning

confidence: 99%

The molecular characteristics of spinal cord gliomas with or without H3 K27M mutation

Chai

Zhang

Liu

et al. 2020

acta neuropathol commun

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Due to the rare incidence of spinal cord astrocytomas, their molecular features remain unclear. Here, we characterized the landscapes of mutations in H3 K27M, isocitrate dehydrogenase 1 (IDH1) R132H, BRAF V600E, and the TERT promoter in 83 diffuse spinal cord astrocytic tumors. Among these samples, thirty-five patients had the H3 K27M mutation; this mutant could be observed in histological grade II (40%), III (40%), and IV (20%) astrocytomas. IDH1 mutations were absent in 58 of 58 cases tested. The BRAF V600E mutation (7/57) was only observed in H3-wildtype astrocytomas, and was associated with a better prognosis in all histological grade II/III astrocytomas. TERT promoter mutations were observed in both H3 K27M-mutant (4/25) and-wildtype (9/33) astrocytomas, and were associated with a poor prognosis in H3-wildtype histological grade II/III astrocytomas. In the 2016 WHO classification of CNS tumors, H3 K27M-mutant diffuse midline gliomas, including spinal cord astrocytomas, are categorized as WHO grade IV. Here, we noticed that the median overall survival of histological grade II/III H3 K27M-mutant cases (n = 28) was significantly longer than that of either the total histological grade IV cases (n = 12) or the H3 K27M-mutant histological grade IV cases (n = 7). We also directly compared H3 K27M-mutant astrocytomas to H3-wildtype astrocytomas of the same histological grade. In histological grade II astrocytomas, compared to H3-wildtype cases (n = 37), H3 K27M-mutant patients (n = 14) had showed a significantly higher Ki-67-positive rate and poorer survival rate. However, no significant differences in these parameters were observed in histological grade III and IV astrocytoma patients. In conclusion, these findings indicate that spinal cord astrocytomas are considerably different from hemispheric and brainstem astrocytomas in terms of their molecular profiles, and that the histological grade cannot be ignored when assessing the prognosis of H3 K27M-mutant spinal cord astrocytomas.

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“…Integrating multiple gene markers into a single model would significantly improve the accuracy and robustness of prediction compared with using a single marker. Chai et al analyzed the RNA processing genes in LGGs and identified a 19-gene risk signature, which had better prognostic value than the traditional factors (20). In this study, we developed a risk signature based on intratumoral immune infiltrationrelated genes with the least absolute shrinkage and selection operator (LASSO) Cox regression model and established a nomogram that incorporated the immune-related risk score and clinical factors to predict the survival of LGG patients.…”

Section: L I N I C a L M E D I C I N Ementioning

confidence: 99%

Prognostic and predictive value of an immune infiltration signature in diffuse lower-grade gliomas

Song¹,

Weng²,

Li³

et al. 2020

JCI Insight

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BACKGROUND. Lower-grade gliomas (LGGs) vary widely in terms of the patient's overall survival (OS). There is no current, valid method that could exactly predict the survival. The effects of intratumoral immune infiltration on clinical outcome have been widely reported. Thus, we aim to develop an immune infiltration signature to predict the survival of LGG patients. METHODS. We analyzed 1216 LGGs from 5 public data sets, including 2 RNA sequencing data sets and 3 microarray data sets. Least absolute shrinkage and selection operator (LASSO) Cox regression was used to select an immune infiltration signature and build a risk score. The performance of the risk score was assessed in the training set (329 patients), internal validation set (140 patients), and 4 external validation sets (405, 118, 88, and 136 patients). RESULTS. An immune infiltration signature consisting of 20 immune metagenes was used to generate a risk score. The performance of the risk score was thoroughly verified in the training and validation sets. Additionally, we found that the risk score was positively correlated with the expression levels of TGF-β and PD-L1, which were important targets of combination immunotherapy. Furthermore, a nomogram incorporating the risk score, patient's age, and tumor grade was developed to predict the OS, and it performed well in all the training and validation sets (C-index: 0.873, 0.881, 0.781, 0.765, 0.721, and 0.753). CONCLUSION. The risk score based on the immune infiltration signature has reliable prognostic and predictive value for patients with LGGs and is a potential biomarker for the cotargeting immunotherapy.

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RNA processing genes characterize RNA splicing and further stratify lower-grade glioma

Cited by 21 publications

References 55 publications

Gene Expression Profiling Stratifies IDH-Wildtype Glioblastoma With Distinct Prognoses

Gene Expression Profiling Stratifies IDH-Wildtype Glioblastoma With Distinct Prognoses

The molecular characteristics of spinal cord gliomas with or without H3 K27M mutation

Prognostic and predictive value of an immune infiltration signature in diffuse lower-grade gliomas

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