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Bao Z.-S.,Beijing Neurosurgical Institute | Bao Z.-S.,Capital Medical University | Bao Z.-S.,Chinese Glioma Cooperative Group CGCG | Chen H.-M.,Peking University | And 43 more authors.
Genome Research | Year: 2014

Studies of gene rearrangements and the consequent oncogenic fusion proteins have laid the foundation for targeted cancer therapy. To identify oncogenic fusions associated with glioma progression, we catalogued fusion transcripts by RNA-seq of 272 gliomas. Fusion transcripts were more frequently found in high-grade gliomas, in the classical subtype of gliomas, and in gliomas treated with radiation/temozolomide. Sixty-seven in-frame fusion transcripts were identified, including three recurrent fusion transcripts: FGFR3-TACC3, RNF213-SLC26A11, and PTPRZ1-MET (ZM). Interestingly, the ZM fusion was found only in grade III astrocytomas (1/13; 7.7%) or secondary GBMs (sGBMs, 3/20; 15.0%). In an independent cohort of sGBMs, the ZM fusion was found in three of 20 (15%) specimens. Genomic analysis revealed that the fusion arose from translocation events involving introns 3 or 8 of PTPRZ and intron 1 of MET. ZM fusion transcripts were found in GBMs irrespective of isocitrate dehydrogenase 1 (IDH1) mutation status. sGBMs harboring ZM fusion showed higher expression of genes required for PIK3CA signaling and lowered expression of genes that suppressed RB1 or TP53 function. Expression of the ZM fusion was mutually exclusive with EGFR overexpression in sGBMs. Exogenous expression of the ZM fusion in the U87MG glioblastoma line enhanced cell migration and invasion. Clinically, patients afflicted with ZM fusion harboring glioblastomas survived poorly relative to those afflicted with non-ZM-harboring sGBMs (P < 0.001). Our study profiles the shifting RNA landscape of gliomas during progression and reveled ZM as a novel, recurrent fusion transcript in sGBMs. © 2014 Bao et al.


PubMed | Capital Medical University, Shenyang University and Chinese Glioma Cooperative Group CGCG
Type: Journal Article | Journal: Journal of neurosurgery | Year: 2016

OBJECTIVE Glioblastoma (GBM) is the most common and lethal type of malignant glioma. The Cancer Genome Atlas divides the gene expression-based classification of GBM into classical, mesenchymal, neural, and proneural subtypes, which is important for understanding GBM etiology and for designing effective personalized therapy. Signal transducer and activator of transcription 3 (STAT3), a critical transcriptional activator in tumorigenesis, is persistently phosphorylated and associated with an unfavorable prognosis in GBM. Although a set of specific targets has been identified, there have been no systematic analyses of STAT3 signaling based on GBM subtype. METHODS This study compared STAT3-associated messenger RNA, protein, and microRNA expression profiles across different subtypes of GBM. RESULTS The analyses revealed a prominent role for STAT3 in the mesenchymal but not in other GBM subtypes, which can be reliably used to classify patients with mesenchymal GBM into 2 groups according to phosphorylated STAT3 expression level. Differentially expressed genes suggest an association between Notch and STAT3 signaling in the mesenchymal subtype. Their association was validated in the U87 cell, a malignant glioma cell line annotated as mesenchymal subtype. Specific associated proteins and microRNAs further profile the STAT3 signaling among GBM subtypes. CONCLUSIONS These findings suggest a prominent role for STAT3 signaling in mesenchymal GBM and highlight the importance of identifying signaling pathways that contribute to specific cancer subtypes.


Ning X.,Tianjin Medical University | Shi Z.,Tianjin Medical University | Shi Z.,Tianjin Neurological Institute | Shi Z.,Key Laboratory of Post trauma Neuro repair and Regeneration in Central Nervous System | And 17 more authors.
Cancer Letters | Year: 2015

Aberrant expression of the microRNA-200 (miR-200) family has been linked to the occurrence and development of various types of malignant tumors, including hepatocellular carcinoma (HCC), colon cancer and breast cancer. However, little is known about the precise mechanism by which miR-200 expression is downregulated. The intricate relationship between DNA methylation and histone modifications has become a subject of increasing interest. The expression of miR-200 family members is modified by similar or complementary epigenetic mechanisms in MGC-803 and BGC-823 gastric cancer cells and U87 MG glioma cells. Chromatin immunoprecipitation assays revealed that DNA methyltransferase 1 (DNMT1) bound to miR-200b/a/429 promoter regions, indicating an interaction between DNMT1 and the miR-200b/a/429 promoter. Furthermore, Co-Immunoprecipitation (Co-IP) detection showed that DNMT1, together with the PcG protein Enhancer of Zeste homolog 2 (EZH2), a histone methyltransferase, contributed to the transcriptional repression of microRNA-200 family members. Knockdown of EZH2 not only impacted H3K27 trimethylation but also reduced DNMT1 presence on the miR-200b/a/429 promoter. EZH2 appeared to be essential for DNMT1 recruitment to the promoter region. Silencing EZH2 and DNMT1 using drugs or RNA interference dramatically reduced the levels of miR-200b/a/429 expression. Collectively, these results indicated that EZH2 and DNMT1-mediated epigenetic silencing contributed to the progression of gastric cancer and glioblastoma, and therefore represents a novel therapeutic target for malignant tumors. © 2015 Elsevier Ireland Ltd.


Zhang J.-X.,Tianjin Medical University | Zhang J.-X.,Nanjing Medical University | Zhang J.-X.,Chinese Glioma Cooperative Group CGCG | Zhang J.,Chinese Academy of Sciences | And 15 more authors.
Neuro-Oncology | Year: 2013

BackgroundAberrant activation of beta-catenin/TCF4 and STAT3 signaling in glioblastoma multiforme (GBM) has been reported. However, the molecular mechanisms related to this process are still poorly understood.MethodsGenome- wide screening of the binding characteristics of the transcription factors TCF4 and STAT3 in GBM cells was performed by chromatin immunoprecipitation sequencing (ChIP-seq) assay. Hierarchical clustering was used to analyze the association of TCF4 and STAT3 coregulated genes with The Cancer Genome Atlas (TCGA) GBM subtypes (classical, mesenchymal, neural, and proneural). New molecular classification of GBM was proposed and validated in Western and Asian populations.ResultsWe identified 1250 overlapping putative target genes that were coregulated by TCF4 and STAT3. Further, the coregulated genes had the potential to guide TCGA GBM subtypes. Finally, we proposed a new molecular classification of GBM into 2 subtypes (proneural-like and mesenchymal-like) and showed that the new classification could be applied to both Western and Asian populations. In addition, the GBM response to temozolomide therapy differed depending on its subtype; mesenchymal-like GBM benefited, while there was no benefit for proneural-like GBM.ConclusionsThis is the first comprehensive study to combine a ChIP-seq assay of TCF4 and STAT3 and data mining of patient cohorts to derive molecular subtypes of GBM. © 2013 The Author(s).


Cai J.,Harbin Medical University | Cai J.,Chinese Glioma Cooperative Group CGCG | Chen J.,Capital Medical University | Chen J.,Chinese Glioma Cooperative Group CGCG | And 20 more authors.
Oncotarget | Year: 2015

Loss of ATRX leads to epigenetic alterations, including abnormal levels of DNA methylation at repetitive elements such as telomeres in murine cells. We conducted an extensive DNA methylation and mRNA expression profile study on a cohort of 82 patients with astrocytic tumors to study whether ATRX expression was associated with DNA methylation level in astrocytic tumors and in which cellular functions it participated.We observed that astrocytic tumors with lower ATRX expression harbored higher DNA methylation level at chromatin end and astrocytic tumors with ATRX-low had distinct gene expression profile and DNA methylation profile compared with ATRX-high tumors. Then, we uncovered that several ATRX associated biological functions in the DNA methylation and mRNA expression profile (GEP), including apoptotic process, DNA-dependent positive regulation of transcription, chromatin modification, and observed that ATRX expression was companied by MGMT methylation and expression. We also found that loss of ATRX caused by siRNA induced apoptotic cells increasing, reduced tumor cell proliferation and repressed the cell migration in glioma cells.Our results showed ATRX-related regulatory functions of the combined profiles from DNA methylation and mRNA expression in astrocytic tumors, and delineated that loss of ATRX impacted biological behaviors of astrocytic tumor cells, providing important resources for future dissection of ATRX role in glioma.


Cai J.,Harbin Medical University | Cai J.,Chinese Glioma Cooperative Group CGCG | Yang P.,Capital Medical University | Yang P.,Chinese Glioma Cooperative Group CGCG | And 19 more authors.
Oncotarget | Year: 2014

Astrocytic tumors are the most common primary brain tumors in adults. ATRX mutations have been identified in gliomas and are correlated with its loss of expression, which causes alternative lengthening of telomeres (ALT) leading to genomic instability. In this study, we aimed to explore the role of ATRX mRNA expression alteration in the progression and subclassification of astrocytic tumors and examine its impact on clinical outcome. We investigated ATRX mRNA expression and its association with IDH1 and IDH2 mutations in 169 adult astrocytic tumors using whole transcriptome sequencing. In our cohort, low ATRX mRNA expression was detected in 68% of astrocytomas, 50% of anaplastic astrocytomas and 41.6% of glioblastomas. Low ATRX expression closely overlapped with mutations in IDH1/2 (P<0.0001) in astrocytic tumors across WHO grades II-IV. Significant association between low ATRX expression and longer overall survival was identified in our cohort (P<0.01). ATRX combined with IDH1/2 and Ki-67 was used to re-classify patients with astrocytic tumors: group A1 containing IDH1/2 mutations and low ATRX expression predicted a better prognostic outcome, whereas group A3 carrying wild-type IDH1/2 and high Ki-67 expression had the shortest overall survival; IDH-mutant tumors with low ATRX expression and IDH-wild-type tumors with high Ki-67 expression were grouped into group A2. In summary, our results showed that ATRX in cooperation with IDH1/2 and Ki-67 defines three subgroups of astrocytic tumors regardless of the conventional WHO grades consensus. The molecular stratification in astrocytic tumors may aid in treatment strategy selection, therapeutic trial design, and clinical prognosis evaluation.


Zhang J.,Tianjin Medical University | Zhang J.,Nanjing Medical University | Zhang J.,Chinese Glioma Cooperative Group CGCG | Chen L.,Tianjin Medical University | And 9 more authors.
Cancer Letters | Year: 2015

The identification of single or less genes based on mRNA expression as clinical diagnostic markers for glioblastoma (GBM) remains a challenge. Recent data have shown the potential oncogenic role and prognostic significance of EZH2 in several human cancers. However, the clinical signature and further mechanisms of EZH2 function in gliomagenesis are still poorly understood. In this study, we found that increased EZH2 expression was associated with tumor grade. High expression of EZH2 in GBM was determined to be a strong and independent predictor of short overall survival. Further, we screened EZH2 targets and associated genes in GBM. Repression of EZH2 induced cell cycle arrest and inhibited tumor growth in vivo. This event represents a positive feedback loop with β-catenin/TCF4 and STAT3 signaling. Taken together, EZH2 could be an independent prognostic factor and potential therapeutic target for GBM. © 2014.


Shi Z.,Tianjin Medical University | Shi Z.,Key Laboratory of Neurotrauma | Shi Z.,Chinese Glioma Cooperative Group CGCG | Zhang J.,Tianjin Medical University | And 25 more authors.
Cancer Research | Year: 2013

The extensive involvement of miRNAs in cancer pathobiology has opened avenues for drug development based on oncomir inhibition. Dicer is the core enzyme in miRNA processing that cleaves the terminal loop of precursor microRNAs (pre-miRNAs) to generate mature miRNA duplexes. Using the three-dimensional structure of the Dicer binding site on the pre-miR-21 oncomir, we conducted an in silico high-throughput screen for small molecules that block miR-21 maturation. By this method, we identified a specific small-molecule inhibitor of miR-21, termed AC1MMYR2, which blocked the ability of Dicer to process pre-miR-21 to mature miR-21. AC1MMYR2 upregulated expression of PTEN, PDCD4, and RECK and reversed epithelial-mesenchymal transition via the induction of E-cadherin expression and the downregulation of mesenchymal markers, thereby suppressing proliferation, survival, and invasion in glioblastoma, breast cancer, and gastric cancer cells. As a single agent in vivo, AC1MMYR2 repressed tumor growth, invasiveness, and metastasis, increasing overall host survival with no observable tissue cytotoxicity in orthotopic models. Our results offer a novel, high-throughput method to screen for small-molecule inhibitors of miRNA maturation, presenting AC1MMYR2 as a broadly useful candidate antitumor drug. ©2013 AACR.


PubMed | Capital Medical University and Chinese Glioma Cooperative Group CGCG
Type: Journal Article | Journal: Genes, chromosomes & cancer | Year: 2016

Oligodendrogliomas (ODs) are the second most common malignant brain tumor and exhibit characteristic co-deletion of chromosomal arms 1p and 19q (co-deletion 1p/19q), which is associated with down-regulation of tumor suppressors. However, co-deletion 1p/19q indicates a favorable prognosis that cannot be explained by the down-regulation of tumor suppressors. In the present study, we determined that co-deletion 1p/19q was associated with reduced Ki-67 protein level based on analysis of 354 ODs. To identify genes associated with reduced Ki-67 and a favorable prognosis of codeletion 1p/19q, we analyzed 96 ODs with RNA-sequencing and 136 ODs and 4 normal brain tissue samples with RNA microarrays. We thus identified seven genes within chromosomal arms 1p/19q with significantly reduced expression in samples with co-deletion of 1p/19q compared to samples with intact 1p/19q. A significant positive correlation was observed between these candidate genes and Ki-67 expression based on analysis of mRNA expression in 305 gliomas and 5 normal brain tissue samples. Survival analysis confirmed the prognostic value of these candidate genes. This finding suggests that these genes within chromosomal arms 1p/19q are associated with low Ki-67 and a favorable prognosis in ODs with co-deletion 1p/19q and provides novel therapeutic targets.


PubMed | Capital Medical University, Southern Medical University and Chinese Glioma Cooperative Group CGCG
Type: Journal Article | Journal: Oncotarget | Year: 2016

Increasing evidence suggests that ion channels not only regulate electric signaling in excitable cells but also play important roles in the development of brain tumor. However, the roles of ion channels in glioma remain controversial. In the present study, we systematically analyzed the expression patterns of ion channel genes in a cohort of Chinese patients with glioma using RNAseq expression profiling. First, a molecular signature comprising three ion channel genes (KCNN4, KCNB1 and KCNJ10) was identified using Univariate Cox regression and two-tailed students t test conducted in overall survival (OS) and gene expression. We assigned a risk score based on three ion channel genes to each primary Glioblastoma multiforme (pGBM) patient. We demonstrated that pGBM patients who had a high risk of unfavorable outcome were sensitive to chemotherapy. Next, we screened the three ion genes-based signature in different molecular glioma subtypes. The signature showed a Mesenchymal subtype and wild-type IDH1 preference. Gene ontology (GO) analysis for the functional annotation of the signature showed that patients with high-risk scores tended to exhibit the increased expression of proteins associated with apoptosis, immune response, cell adhesion and motion and vasculature development. Gene Set Enrichment Analysis (GSEA) results showed that pathways associated with negative regulation of programmed cell death, cell proliferation and locomotory behavior were highly expressed in the high-risk group. These results suggest that ion channel gene expression could improve the subtype classification in gliomas at the molecular level. The findings in the present study have been validated in two independent cohorts.

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