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Background: High-grade gliomas (HGGs) have a rapid relapse and short survival. Studies have identified many clinical characteristics and biomarkers associated with progression-free survival (PFS) and over-survival (OS). However, there has not yet a comprehensive study on survival after the first progression (SAP). Methods: From CGGA and TCGA, 319 and 308 HGGs were confirmed as the first progression. The data on clinical characteristics and biomarkers were analyzed in accordance with OS, PFS, and SAP. Results: Analysis of 319 patients from CGGA, significant predictors of improved OS/PFS/SAP were WHO grade, MGMT promoter methylation, and Ki-67 expression in univariate analysis. Further multivariate analysis showed MGMT promoter methylation and Ki-67 expression were independent predictors. However, an analysis of 308 patients from TCGA found MGMT promoter methylation is the only prognostic marker. A longer SAP was observed in patients with methylated MGMT promoter after standard chemoradiotherapy. In our data, HGGs could be divided into low, intermediate, and high-risk groups for SAP by MGMT methylation and Ki-67 expression. Conclusions: Patients with MGMT promoter methylation have a prolonger SAP after standard chemoradiotherapy. HGGs could be divided into low, intermediate, and high-risk groups for SAP according to MGMT status and Ki-67 expression. [ABSTRACT FROM AUTHOR]

Objective: Radiotherapy (RT) is a cornerstone of the glioblastoma (GBM) treatment. However, the resistance of tumour cells to radiation results in early recurrence. The mechanisms underlying GBM radioresistance remain unclear. Screening for differentially expressed genes (DEGs) related to radiation might be a potential solution to this problem. Method: RT‐associated DEGs were screened based on the RNA sequencing of 15 paired primary and recurrent GBMs. The mRNA and protein expression of candidate genes were validated in RNA sequencing of The Chinese Genome Atlas (CGGA) dataset and 18 cases of GBM samples. The relationship between the candidate gene and radiation was confirmed in irradiated GBM cells. The association of candidate gene with clinical characteristics and survival was investigated in the CGGA and TCGA dataset. Biological function and pathway analysis were explored by gene ontology analysis. The association of the candidate gene with radiosensitivity was verified using cell counting Kit‐8, comet, and colony formation assays in vitro and subcutaneous tumour xenograft experiments in vivo. Results: Gelsolin (GSN) was selected for further study. GSN expression was significant elevated in recurrent GBM and up‐regulated in irradiated GBM cell lines. High expression of GSN was enriched in malignant phenotype of glioma. Moreover, high expression of GSN was associated with poor prognosis. Further investigation demonstrated that GSN‐knockdown (GSN‐KD) combined with RT significantly inhibited cell proliferation and enhanced radiosensitivity in vivo and in vitro. Mechanistically, GSN‐KD could lead to more serious DNA damage and promotes apoptosis after RT. Conclusion: Radiation induced up‐regulated of GSN. GSN‐KD could enhance the radiosensitivity of GBM. [ABSTRACT FROM AUTHOR]

Polymerase I and transcript release factor (PTRF) plays a role in the regulation of gene expression and the release of RNA transcripts during transcription, which have been associated with various human diseases. However, the role of PTRF in glioma remains unclear. In this study, RNA sequencing (RNA-seq) data (n = 1022 cases) and whole-exome sequencing (WES) data (n = 286 cases) were used to characterize the PTRF expression features. Gene ontology (GO) functional enrichment analysis was used to assess the biological implication of changes in PTRF expression. As a result, the expression of PTRF was associated with malignant progression in gliomas. Meanwhile, somatic mutational profiles and copy number variations (CNV) revealed the glioma subtypes classified by PTRF expression showed distinct genomic alteration. Furthermore, GO functional enrichment analysis suggested that PTRF expression was associated with cell migration and angiogenesis, particularly during an immune response. Survival analysis confirmed that a high expression of PTRF is associated with a poor prognosis. In summary, PTRF may be a valuable factor for the diagnosis and treatment target of glioma. [ABSTRACT FROM AUTHOR]

Diffuse gliomas (DGs) are the most common and lethal primary neoplasms in the central nervous system. The latest 2021 World Health Organization (WHO) Classification of Tumors of the Central Nervous System (CNS) was published in 2021, immensely changing the approach to diagnosis and decision making. As a part of the Chinese Glioma Genome Atlas (CGGA) project, our aim was to provide genomic profiling of gliomas in a Chinese cohort. Two hundred eighty six gliomas with different grades were collected over the last decade. Using the Illumina HiSeq platform, over 75.8 million high-quality 150 bp paired-end reads were generated per sample, yielding a total of 43.4 billion reads. We also collected each patient's clinical and pathological information and used it to annotate their genetic data. All patients were diagnosed and classified by neuro-pathologist under the 2021 WHO classification. This dataset provides an important reference for researchers and will significantly advance our understanding of gliomas. Measurement(s) glioma Technology Type(s) Whole Exome Sequencing Sample Characteristic - Organism Homo sapiens [ABSTRACT FROM AUTHOR]

Background: The radiation dose for patients with low‐grade gliomas (LGGs) is controversial. The objective of this study was to investigate the impact of the radiation dose on survival for patients with LGGs and especially for molecularly defined subgroups. Methods: Three hundred fifty‐one patients with newly diagnosed LGGs from the multicenter Chinese Glioma Cooperative Group received postoperative radiotherapy (RT) in 2005‐2018. The RT dose, as a continuous variable, was entered into a Cox regression model using penalized spline regression to allow for a nonlinear relationship between the RT dose and overall survival (OS) or progression‐free survival (PFS). Inverse probability of treatment weighting (IPTW)–adjusted propensity scores were used to correct for potential confounders. Dose effects on survival within IDH mutation and 1p/19q codeletion defined subgroups were analyzed. Results: The risk of mortality and disease progression decreased sharply until 54 Gy. High‐dose RT (≥54 Gy) was associated with significantly better 5‐year OS (81.7% vs 64.0%; hazard ratio [HR], 0.33; P <.001) and PFS (77.4% vs 54.5%; HR, 0.46; P <.001) than low‐dose RT (<54 Gy). IPTW correction confirmed the associations (HR for OS, 0.44; P =.001; HR for PFS, 0.48; P =.003). High‐dose RT was associated with longer PFS (HR, 0.25; P =.002; HR, 0.21; P =.039) and OS (HR, 0.27; P =.006; HR, 0.07; P =.017) in IDH‐mutant/1p/19q noncodeleted and IDH wild‐type subgroups, respectively. No significant difference in survival was observed with high‐dose RT in the IDH‐mutant/1p/19q codeleted subgroup. Conclusions: High‐dose RT (≥54 Gy) was effective in LGGs. Patients with an IDH mutation/1p/19q noncodeletion or IDH wild‐type may need to be considered for high‐dose RT. Lay Summary: The radiotherapy dose‐response was observed in patients with low‐grade gliomas, and high‐dose radiotherapy (≥54 Gy) was associated with improved survival.Patients with an IDH mutation/1p/19q noncodeletion or wild‐type IDH may have improved survival with the administration of high‐dose radiotherapy. High‐dose radiotherapy (≥54 Gy) is an independent protective factor for overall survival and progression‐free survival in low‐grade gliomas. Patients with an IDH mutation/1p/19q noncodeletion or IDH wild‐type benefit from high‐dose radiotherapy. [ABSTRACT FROM AUTHOR]

Background: Patients with low-grade gliomas (LGGs) harboring O6-methylguanine-DNA methyltransferase promoter nonmethylation (MGMT-non-pM) have a particularly short survival and are great resistance to chemotherapy. The objective of this study was to assess the efficacy of high-dose radiotherapy (RT) for LGGs with MGMT-non-pM.Methods: 268 patients with newly diagnosed adult supratentorial LGGs from the multicenter Chinese Glioma Cooperative Group (CGCG) received postoperative RT during 2005-2018. MGMT promoter methylation analysis was conducted by pyrosequencing in all patients. Univariate and multivariate analysis were performed using the Cox regression to determine the prognostic factors for overall survival (OS) and progression-free survival (PFS). RT dose-response on MGMT status defined subtypes was analyzed.Results: On univariate analysis, the following were statistically significant favorable factors for both PFS and OS: oligodendrogliomas(p = 0.002 and p = 0.005), high-dose RT (> 54 Gy) (p = 0.021 and p = 0.029) and 1p/19q codeletion (p < 0.001 and p = 0.001). On multivariate analysis, RT dose (> 54 Gy vs. ≤ 54 Gy) and IDH mutation were independently prognostic markers for OS (HR, 0.47; 95%CI, 0.22-0.98; p = 0.045; and HR, 0.44; 95%CI, 0.21-0.96; p = 0.038, respectively) and PFS (HR, 0.48; 95%CI, 0.26-0.90; p = 0.022; and HR, 0.51; 95%CI, 0.26-0.98; p = 0.044, respectively). High-dose RT was associated with longer OS (HR, 0.56; 95%CI, 0.32-0.96; p = 0.036) and PFS (HR, 0.58; 95%CI, 0.35-0.96; p = 0.033) than low-dose RT in MGMT-non-pM subtype. In contrast, no significant difference in either OS (p = 0.240) or PFS (p = 0.395) was observed with high-dose RT in the MGMT-pM subtype.Conclusions: High-dose RT (> 54 Gy) is an independently protective factor for LGGs and is associated with improved survival in patients with MGMT-non-pM. [ABSTRACT FROM AUTHOR]

Purpose: Current studies and guidelines suggest that the biobehavior of IDH-wild type (IDH-wt) lower-grade glioma (LGG, WHO II-III) is similar to IDH-wt glioblastoma (GBM). However, differences in their clinical and molecular characteristics have not been reported. This study aimed to analyze the clinical and genetic information of gliomas with IDH-wt. Methods: 389 patients with IDH-wt were enrolled in the study (LGG=165, GBM=224), and their clinical and genetic information was collected from the Chinese Glioma Genome Atlas (CGGA). We conducted an analysis of this information between the two groups of patients and drew conclusions thereof. Results: The median age of the LGG patients was 42 (18–74) years, whereas that of the GBM patients was 51 (18–79) years (P < 0.010). GBM patients were more likely to undergo total resection (P = 0.018) and had fewer epileptic seizure symptoms (P < 0.001). The median overall survival (OS) was 55 months for the LGG patients and only 14.83 months for the GBM patients (P < 0.01). The median progression-free survival (PFS) was 44 months for the LGG patients and only 9.767 months for the GBM patients (P < 0.001). GBM patients were more prone to PETN mutations (P = 0.010). Transcriptome analysis showed that the differentially expressed genes in LGG patients were mainly enriched in metabolic pathways and pathways in cancer and in the function of signal transduction and positive regulation of GTPase activity, whereas in GBM patients, they were mainly enriched in the PI3K-Akt signaling pathway and in the functions of apoptotic process and oxidation-reduction process. Conclusions: Our data indicate that these two groups of patients should be re-evaluated and treated differently, despite both having IDH wild type. [ABSTRACT FROM AUTHOR]

Background: PTPRZ1‐MET (ZM) is a critical genetic alteration driving the progression of lower‐grade glioma. Glioma patients harboring ZM could benefit from MET inhibitors. According to the remarkable role of ZM as a driver of glioma progression and indicator of MET inhibitor sensitivity, it is necessary to detect this alteration even when it presents in glioma with relatively fewer copies. Methods: Herein, we proposed that ZM could be detected with a high‐sensitive method of reverse transcriptase PCR with 50 amplification cycles. Via this newly proposed detection method, we depicted the incidence preference of ZM fusion in a cohort of 485 glioma patients. To further explore the oncogenic nature of ZM, we predicated the protein structure alteration of MET kinase brought by its fusion partner. Results: The incidence of ZM fusions was much higher than previous report. ZM fusions exhibited a striking preference in lower‐grade glioma and secondary glioblastoma. By contrast, none of patients with primary glioblastoma was detected harboring ZM fusion. In each of the four variants of ZM, the fusion partner segment of MET contained a remarkable coiled‐coil motif. In glioma cells expressing ZM, MET kinase could be activated in a ligand‐independent manner, which might be contributed by the special coiled‐coil structure brought by the fusion partner. Corresponding to the 3D structural analysis and cell line experiment, the ZM positive clinical specimens showed hyperactivations of MET signaling. Conclusions: ZM fusions are critical drivers of glioma progression and effective target of MET inhibitor. Early detection could be performed with a high‐sensitive method of reverse transcriptase PCR. The hyperactivations of MET signaling driving glioma progression might be contributed by a ligand‐independent activation enabled by the protein structure modification of extracellular domain of MET in ZM fusions. [ABSTRACT FROM AUTHOR]

Background: RGS protein family members have recently became new potentially promising therapeutic targets in many cancers. However, as a key member of RGS family, RGS16 has seldom been studied in glioma. The present study was designed to investigate the prognostic value and biological function of RGS16 based on large‐scale databases and functional assays in vitro. Methods: Here, we performed comprehensive analysis for the expression characteristic of RGS16 in Chinese Glioma Genome Atlas (CGGA) microarray database with 301 patients and validated in The Cancer Genome Atlas (TCGA) microarray and RNA sequencing database. Student's t‐test, one‐way ANOVA test and long‐rank test were used to assess differences between groups. Kaplan‐Meier survival, univariate and multivariate Cox analysis and ROC curve were used to estimate the survival distributions. Biological implication of abnormal expression of RGS16 in glioma was also explored. Functional analysis of RGS16 was performed in several glioblastoma (GBM) cell lines. R language and SPSS were used for statistical analysis and graphical work. Results: We found that the expression of RGS16 was positively related to the grade of glioma. High level of RGS16 commonly gathered in glioma of mesenchymal subtype and wild‐type IDH1. Moreover, higher expression level of RGS16 was found to be significantly correlated with poor prognosis. The univariate and multivariate Cox regression analysis and ROC curve showed that RGS16 was an independent prognostic factor for glioma patients. Gene ontology analysis, gene set enrichment analysis, and gene set variation analysis suggested that the overexpression of RGS16 tightly related to cell proliferation, migration, epithelial‐mesenchymal transition (EMT), immune and inflammatory response of glioma. Knockdown of RGS16 in glioma cell lines also showed that RGS16 promoted the malignant progress of glioma cell lines. Conclusions: RGS16 plays an important role in glioma progression and serves as an independent prognostic factor, especially in GBM patients. [ABSTRACT FROM AUTHOR]

Glioma is the most common primary intracranial tumor and is associated with very low survival rates. The development of reliable biomarkers can help to elucidate the molecular mechanisms involved in glioma development. Here the expression of ABCC8 mRNA, clinical characteristics, and survival information based on 1893 glioma samples from four independent databases were analyzed. The expression patterns of ABCC8 mRNA were compared by a Chi square test. The overall survival rate of gliomas was evaluated according to the expression level of ABCC8 mRNA. The prognostic value of this marker in gliomas was tested using Cox single factor and multi factor regression analyses. We found patients with low WHO grade, oligodendrocytoma, low molecular grade, IDH mutation, and 1p19q combined deletion had high ABCC8 mRNA expression. The patients with high expression of ABCC8 mRNA had longer survival. ABCC8 mRNA expression was a new independent prognostic index for glioma. Temozolomide chemotherapy was an independent index to prolong overall survival in high ABCC8 mRNA expression glioma patients, whereas in patients with low expression, there was no significant difference. So ABCC8 mRNA expression could be an independent prognostic indicator for glioma patients and could predict the sensitivity of glioma to temozolomide. [ABSTRACT FROM AUTHOR]

Glioblastoma multiforme (GBM) is the most common and malignant type of glioma, with a poor prognosis for patients. The survival time of patients varies greatly due to the complexity of the human genome, which harbors diverse oncogenic drivers. In order to identify the specific driving factors, 325 glioma samples from the Chinese Glioma Genome Atlas (CGGA) database were analyzed in the present study. The level of RELB proto-oncogene, NF-κβ subunit (RELB) expression increased with the pathological grade progression of the gliomas, and higher expression levels were present in the mesenchymal subtype and isocitrate dehydrogenase 1 (IDH1) wild-type gliomas. This RELB expression pattern was identified in the CGGA database and observed in three large independent databases. In patients with GBM from the CGGA database, a higher RELB expression level was associated with a shorter survival time, a mesenchymal subtype and IDH1 wild-type gliomas. Kaplan-Meier survival analysis, survival nomograms and Cox analysis demonstrated an independent prognostic value for RELB expression. Moreover, biological function analysis indicated the association of RELB with the 'immune response', 'cell activation' and the 'apoptotic process'. In addition, RELB expression levels exhibited a negative correlation with the levels of microRNA (miR)-139-5p and miR-139-3p. The present study identified the pathological and biological roles of RELB in glioma and revealed its independent prognostic effect. These results suggested that RELB may be used as a prognostic biomarker and potential therapeutic target in glioma. [ABSTRACT FROM AUTHOR]

Glioma is the most common primary brain tumor with various genetic alterations; among which, IDH mutation is the most common mutation and plays an important role in glioma early development, especially in lower grade glioma (LGG, WHO II-III). Previous studies have found that IDH mutation is tightly associated with extensive methylation across whole genome in glioma. To further investigate the role of IDH, we obtained methylation data of 777 samples from CGGA (Chinese Glioma Genome Atlas) and TCGA (The Cancer Genome Atlas) with IDH mutation status available. A package compiled under R language called Tspair was used as the main analytic tool to find potential probes that were significantly affected by IDH mutation. As a result, we found one pair of probes, cg06940792 and cg26025891, which was capable of predicting IDH mutation status precisely. The hypermethylated probe was cg06940792, designed in the promoter region of MEGF10, while the hypomethylated probe was cg26025891, designed in the promoter region of PSTPIP1. Survival analysis proved that hypermethylation or low expression of MEGF10 indicated a favorable prognosis in 983 glioma samples. Moreover, gene ontology analysis demonstrated that MEGF10 was associated with cell migration, cell proliferation, and regulation of apoptosis in glioma. All findings above can be validated in three other independent cohorts. In a word, our results suggested that methylation level and mRNA expression of MEGF10 in glioma were not only correlated with IDH mutation but also associated with clinical outcome of patients, providing potential guide for future dissection of IDH role in glioma. [ABSTRACT FROM AUTHOR]

Purpose: Primary glioblastoma (pGBM) is the most common and lethal type of neoplasms in the central nervous system, while the existing biomarkers, lacking consideration on the stemness changes of GBM cells, are not specific enough to predict the complex prognosis respectively. We aimed to build a high-efficiency prediction gene signature related to GBM cell stemness and investigate its prognostic value in primary glioblastoma.Methods: Differentially expressed genes were screened in GSE23806 database. The selected genes were then verified by univariate Cox regression in 591 patients from four enormous independent databases, including the Chinese Glioma Genome Atlas (CGGA), TCGA, REMBRANDT and GSE16011. Finally, the intersected genes were included to build the gene signature. GO analysis and GSEA were carried out to explore the bioinformatic implication.Results: The novel five-gene signature was used to identify high- and low-risk groups in the four databases, and the high-risk group showed notably poorer prognosis (P < 0.05). Gene ontology (GO) terms including “immune response”, “apoptotic process”, and “angiogenesis” were picked out by GO analysis and GSEA, which revealed that the gene signature was highly possibly related to the stemness of GSCs and predicting the prognosis of GBM effectively.Conclusion: We built a gene signature with five glioblastoma stem-like cell (GSC) relevant genes, and predicted the survival in four independent databases effectively, which is possibly related to the stemness of GSCs in pGBM. Several GO terms were investigated to be correlated to the signature. The signature can predict the prognosis of glioblastoma efficiently. [ABSTRACT FROM AUTHOR]

Aldehyde dehydrogenases (ALDH) is a family of enzymes including 19 members. For now, ALDH activity had been wildly used as a marker of cancer stem cells (CSCs). But biological functions of relevant isoforms and their clinical applications are still controversial. Here, we investigate the clinical significance and potential function of ALDH1A3 in gliomas. By whole-genome transcriptome microarray and mRNA sequencing analysis, we compared the expression of ALDH1A3 in high- and low- grade gliomas as well as different molecular subtypes. Microarray analysis was performed to identify the correlated genes of ALDH1A3. We further used Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways analysis to explore the biological function of ALDH1A3. Finally, by mRNA knockdown we revealed the relationship between ALDH1A3 and the ability of tumor invasion. ALDH1A3 overexpression was significantly associated with high grade as well as the higher mortality of gliomas in survival analysis. ALDH1A3 was characteristically highly expressed in Mesenchymal (Mes) subtype gliomas. Moreover, we found that ALDH1A3 was most relevant to extracellular matrix organization and cell adhesion biological process, and the ability of tumor invasion was suppressed after ALDH1A3 knockdown in vitro. In conclusion, ALDH1A3 can serve as a novel marker of Mes phenotype in gliomas with potential clinical prognostic value. The expression of ALDH1A3 is associated with tumor cell invasion. [ABSTRACT FROM AUTHOR]

Glioma, the most common form of primary malignant brain tumors, is graded based solely on histopathological appearance, which has led to prognostic discrepancies. This study aimed to establish a new glioma grading model by analyzing the expression of Bone Morphogenetic Protein 2 (BMP2) mRNA in patients with gliomas as well, named the Histopathological-BMP2 (HB) system. Clinical information was collected from 692 patients from the Chinese Glioma Genome Atlas database. According to pathological glioma subtypes and the expression of BMP2 mRNA in tumor tissues, the new subtypes HBs, HBh, HBm and HB1 were established, with BMP2 expression highest in HBs and lowest in HB1. Survival periods were analyzed. Based on this, the expression of three BMP2 receptors (BMPR1A, BMPR1B, and BMPR2) was also analyzed, which was related to the prognosis of patients. This new classification model was validated in further groups of patients from the CGGA database (n = 291) and the Cancer Genome Atlas (n = 625). A new glioma grade (HB grade) based on histopathology and BMP2 expression can predict the prognosis of glioma patients, with BMPR1B and BMPR2 expression indicating a different prognosis in different types of gliomas. The higher the concentration of BMP2, the better the prognosis of patients. [ABSTRACT FROM AUTHOR]

The comprehensive lncRNA expression signature in glioma has not yet been fully elucidated. We performed a high-throughput microarray to detect the ncRNA expression profiles of 220 human glioma tissues. Here, we found that a novel lncRNA, HOXA11-AS, was the antisense transcript of the HOX11 gene. It was shown that HOXA11-AS was closely associated with glioma grade and poor prognosis. Multivariate Cox regression analysis revealed that HOXA11-AS was an independent prognostic factor in glioblastoma multiforme patients, and its expression was correlated with the glioma molecular subtypes of the Cancer Genome Atlas. Gene set enrichment analysis indicated that the gene sets most correlated with HOXA11-AS expression were involved in cell cycle progression. Over-expression of the HOXA11-AS transcript promoted cell proliferation in vitro, while knockdown of HOXA11-AS expression repressed cell proliferation via regulation of cell cycle progression. The growth-promoting and growth-inhibiting effects of HOXA11-AS were also demonstrated in a xenograft mouse model. Our data confirms, for the first time, that HOXA11-AS is an important long non-coding RNA that primarily serves as a prognostic factor for glioma patient survival. HOXA11-AS could serve as a biomarker for identifying glioma molecular subtypes and as therapeutic target for glioma patients. [ABSTRACT FROM AUTHOR]

Recent studies have revealed that PTPRZ1-MET (ZM) fusion plays a pivotal role in the progression of glioma to glioblastoma multiforme (GBM), thus serving as a biomarker to distinguish between primary GBM and secondary GBM (sGBM). However, the mechanisms through which ZM fusion influences this progression remain to be elucidated. GBMs with ZM showed poorer prognoses and greater infiltration of tumor-associated macrophages (TAMs) than those without ZM. Glioma stem-like cells (GSCs) and TAMs play complex roles in glioma recurrence, glioma progression and therapy resistance. In this study, we analyzed RNA-seq data from sGBM patients' glioma tissues with or without ZM fusion, and found that stemness and macrophage markers were more highly expressed in sGBM patients harboring ZM than in those without ZM fusion. ZM enhanced the self-renewal and proliferation of GSCs, thereby accelerating glioma progression. In addition, ZM-positive GSCs facilitated the infiltration of TAMs and drove their polarization toward an immunosuppressive phenotype, which was primarily accomplished through the extracellular secretion of ISG20. Our research identified the MET–STAT3–ISG20 axis within GSCs, thus demonstrating the critical role of ZM in GBM initiation and progression. Our study demonstrated that, in contrast to ZM-positive differentiated glioma cells, ZM-positive GSCs upregulated ISG20 expression through the MET–STAT3–ISG20 axis. The extracellular secretion of ISG20 recruited and induced M2-like polarization in macrophages, thereby promoting tumor progression. Our results reveal a novel mechanism involved in ZM-positive GBM pathogenesis and identify potential therapeutic targets. Schematic model of the interaction between glioma stem-like cells (GSCs) with PTPRZ1-MET fusion (ZM) and tumor-associated macrophages (TAMs). ZM can induce activation of MET–STAT3–ISG20 axis in GSCs. The overexpressed ISG20 protein is secreted from GSCs with ZM, recruiting TAMs and inducing their M2-like polarization. The M2-like TAMs maintain the stemness of GSCs and promote glioma progression. Inhibiting STAT3 activation in ZM GSCs can block these events. [Display omitted] • Glioma with PTPRZ1-MET (ZM) is rich in glioma stem-like cells (GSCs) and macrophages. • GSCs with ZM (not tumor cells) facilitate immunosuppressive macrophage infiltration. • ZM induces MET – STAT3 – ISG20 axis activation in GSCs, but not in differentiated cells. • ZM induces the overexpression and secretion of ISG20 protein in GSCs. • ISG20-educated macrophages promote glioma progression. [ABSTRACT FROM AUTHOR]

Summary Low-grade gliomas almost invariably progress into secondary glioblastoma (sGBM) with limited therapeutic option and poorly understood mechanism. By studying the mutational landscape of 188 sGBMs, we find significant enrichment of TP53 mutations, somatic hypermutation, MET -exon-14-skipping (MET ex14), PTPRZ1 - MET (ZM) fusions, and MET amplification. Strikingly, MET ex14 frequently co-occurs with ZM fusion and is present in ∼14% of cases with significantly worse prognosis. Subsequent studies show that MET ex14 promotes glioma progression by prolonging MET activity. Furthermore, we describe a MET kinase inhibitor, PLB-1001, that demonstrates remarkable potency in selectively inhibiting MET -altered tumor cells in preclinical models. Importantly, this compound also shows blood-brain barrier permeability and is subsequently applied in a phase I clinical trial that enrolls MET -altered chemo-resistant glioma patients. Encouragingly, PLB-1001 achieves partial response in at least two advanced sGBM patients with rarely significant side effects, underscoring the clinical potential for precisely treating gliomas using this therapy. Graphical Abstract Highlights • Characterization of the mutational landscape of secondary glioblastoma • Clonal and subclonal MET ex14 promote glioma progression and mark worse prognosis • PLB-1001 is a highly selective, efficient, and BBB-permeable MET kinase inhibitor • PLB-1001 provides a safe and efficacious therapeutic approach for glioma treatment A new MET inhibitor shows preliminary efficacy for treatment of patients with secondary glioblastoma. [ABSTRACT FROM AUTHOR]