Verhaak, RG, Hoadley, KA, Purdom, E, Wang, V, Qi, Y, Wilkerson, MD et al.; Cancer Genome Atlas Research Network.. Integrated genomic analysis identifies clinically relevant subtypes of glioblastoma characterized by abnormalities in PDGFRA, IDH1, EGFR, and NF1. Cancer Cell 17: 98-110

The Eli and Edythe L. Broad Institute of Massachusetts Institute of Technology and Harvard University, Cambridge, MA 02142, USA.
Cancer cell (Impact Factor: 23.52). 01/2010; 17(1):98-110. DOI: 10.1016/j.ccr.2009.12.020
Source: PubMed


The Cancer Genome Atlas Network recently cataloged recurrent genomic abnormalities in glioblastoma multiforme (GBM). We describe a robust gene expression-based molecular classification of GBM into Proneural, Neural, Classical, and Mesenchymal subtypes and integrate multidimensional genomic data to establish patterns of somatic mutations and DNA copy number. Aberrations and gene expression of EGFR, NF1, and PDGFRA/IDH1 each define the Classical, Mesenchymal, and Proneural subtypes, respectively. Gene signatures of normal brain cell types show a strong relationship between subtypes and different neural lineages. Additionally, response to aggressive therapy differs by subtype, with the greatest benefit in the Classical subtype and no benefit in the Proneural subtype. We provide a framework that unifies transcriptomic and genomic dimensions for GBM molecular stratification with important implications for future studies.

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    • "In the past decade, transcriptomic and methylation analyses have classified GBM tumors into several subtypes (Phillips et al., 2006; Sturm et al., 2012; Verhaak et al., 2010), including proneural (PN), classical, and mesenchymal (MES) GBMs. While these signatures are based on the predominant gene expression patterns in the tumor and correlate with mutation and epigenetic status, GBMs are very heterogeneous, and data demonstrate the presence of cells of multiple subtypes within a single tumor as well as transitions between subtypes (Bhat et al., 2013; Patel et al., 2014; Piao et al., 2013). "
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    ABSTRACT: Glioblastoma is a highly lethal cancer for which novel therapeutics are urgently needed. Two distinct subtypes of glioblastoma stem-like cells (GSCs) were recently identified: mesenchymal (MES) and proneural (PN). To identify mechanisms to target the more aggressive MES GSCs, we combined transcriptomic expression analysis and kinome-wide short hairpin RNA screening of MES and PN GSCs. In comparison to PN GSCs, we found significant upregulation and phosphorylation of the receptor tyrosine kinase AXL in MES GSCs. Knockdown of AXL significantly decreased MES GSC self-renewal capacity in vitro and inhibited the growth of glioblastoma patient-derived xenografts. Moreover, inhibition of AXL with shRNA or pharmacologic inhibitors also increased cell death significantly more in MES GSCs. Clinically, AXL expression was elevated in the MES GBM subtype and significantly correlated with poor prognosis in multiple cancers. In conclusion, we identified AXL as a potential molecular target for novel approaches to treat glioblastoma and other solid cancers. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.
    Stem Cell Reports 04/2015; 24(5). DOI:10.1016/j.stemcr.2015.03.005 · 5.37 Impact Factor
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    • "The mean and SD values were calculated and analyzed for significance between groups and subtypes. Molecular sub-class was predicted from the subtype metagene score as defined by the Verhaak et al. [12]. Pearson correlation coefficient between the expression of OSMR and subtype molecular signature genes was performed. "
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    ABSTRACT: Glioblastoma (GBM), the most malignant of the brain tumors is classified on the basis of molecular signature genes using TCGA data into four subtypes- classical, mesenchymal, proneural and neural. The mesenchymal phenotype is associated with greater aggressiveness and low survival in contrast to GBMs enriched with proneural genes. The proinflammatory cytokines secreted in the microenvironment of gliomas play a key role in tumor progression. The study focused on the role of Oncostatin-M (OSM), an IL-6 family cytokine in inducing mesenchymal properties in GBM. Analysis of TCGA and REMBRANDT data revealed that expression of OSMR but not IL-6R or LIFR is upregulated in GBM and has negative correlation with survival. Amongst the GBM subtypes, OSMR level was in the order of mesenchymal > classical > neural > proneural. TCGA data and RT-PCR analysis in primary cultures of low and high grade gliomas showed a positive correlation between OSMR and mesenchymal signature genes-YKL40/CHI3L1, fibronectin and vimentin and a negative correlation with proneural signature genes-DLL3, Olig2 and BCAN. OSM enhanced transcript and protein level of fibronectin and YKL-40 and reduced the expression of Olig2 and DLL3 in GBM cells. OSM-regulated mesenchymal phenotype was associated with enhanced MMP-9 activity, increased cell migration and invasion. Importantly, OSM induced mesenchymal markers and reduced proneural genes even in primary cultures of grade-III glioma cells. We conclude that OSM-mediated signaling contributes to aggressive nature associated with mesenchymal features via STAT3 signaling in glioma cells. The data suggest that OSMR can be explored as potential target for therapeutic intervention. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.
    Neoplasia (New York, N.Y.) 02/2015; 17(2):225-37. DOI:10.1016/j.neo.2015.01.001 · 4.25 Impact Factor
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    • "com . ] mutations further stratify glioblastomas ; IDH1 mutations are associated with the proneural phenotype , which includes primary glioblastomas arising from clinically silent lower grade lesions , secondary glioblastomas estab - lished by prior lower - grade histology , and oligodendro - gliomas arising from a progenitor or neural stem cell ( Verhaak et al . , 2010 ) . IDH mutations allow oligodendro - gliomas to be distinguished from astrocytic gliomas ( together with CIC , FUBP1 mutations , p53 mutation / deletion , and 1 / 19q codeletions ; Yip et al . , 2012 ; Fig . 4 ) , nonneoplastic lesions , and therapy - induced changes ( Cap - per et al . , 2010a ) . In gangliogliomas , the presence of m"
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    ABSTRACT: Over the past few years, new biomarkers have allowed a deeper insight into gliomagenesis and facilitated the identification of possible targets for glioma therapy. Isocitrate dehydrogenase (IDH) 1 and IDH2 mutations have been shown to be promising biomarkers for monitoring disease prognosis and predicting the response to treatment. This review summarizes recent findings in this field. Web of Science, Science Direct, and PubMed online databases were used to search for publications investigating the role of IDH in glioma. References were identified by searching for the keywords "IDH1 or IDH2 and glioma and diagnostic or predictive or prognostic" in papers published from January, 2008, to April, 2014. Only papers in English were reviewed. Publications available only as an abstract were not included. IDH1/2 mutations are tightly associated with grade II and III gliomas and secondary glioblastomas, with better prognosis and production of a recently described oncometabolite, 2-hydroxyglutarate (2HG). Although the contradictory positive effect of IDH mutation on prognosis and negative role of 2HG in tumor transformation remain unresolved, the future direction of personalized treatment strategies targeted to glioma development is likely to focus on IDH1/2 mutations. © 2014 Wiley Periodicals, Inc.
    Journal of Neuroscience Research 12/2014; 92(12). DOI:10.1002/jnr.23456 · 2.59 Impact Factor
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