Key points are not available for this paper at this time.
The Cancer Genome Atlas (TCGA) project has generated gene expression data that divides glioblastoma (GBM) into four transcriptional classes: proneural, neural, classical, and mesenchymal. Because transcriptional class is only partially explained by underlying genomic alterations, we hypothesize that the tumor microenvironment may also have an impact. In this study, we focused on necrosis and angiogenesis because their presence is both prognostically and biologically significant. These features were quantified in digitized histological images of TCGA GBM frozen section slides that were immediately adjacent to samples used for molecular analysis. Correlating these features with transcriptional data, we found that the mesenchymal transcriptional class was significantly enriched with GBM samples that contained a high degree of necrosis. Furthermore, among 2422 genes that correlated with the degree of necrosis in GBMs, transcription factors known to drive the mesenchymal expression class were most closely related, including C/EBP-β, C/EBP-δ, STAT3, FOSL2, bHLHE40, and RUNX1. Non-mesenchymal GBMs in the TCGA data set were found to become more transcriptionally similar to the mesenchymal class with increasing levels of necrosis. In addition, high expression levels of the master mesenchymal factors C/EBP-β, C/EBP-δ, and STAT3 were associated with a poor prognosis. Strong, specific expression of C/EBP-β and C/EBP-δ by hypoxic, perinecrotic cells in GBM likely account for their tight association with necrosis and may be related to their poor prognosis. The Cancer Genome Atlas (TCGA) project has generated gene expression data that divides glioblastoma (GBM) into four transcriptional classes: proneural, neural, classical, and mesenchymal. Because transcriptional class is only partially explained by underlying genomic alterations, we hypothesize that the tumor microenvironment may also have an impact. In this study, we focused on necrosis and angiogenesis because their presence is both prognostically and biologically significant. These features were quantified in digitized histological images of TCGA GBM frozen section slides that were immediately adjacent to samples used for molecular analysis. Correlating these features with transcriptional data, we found that the mesenchymal transcriptional class was significantly enriched with GBM samples that contained a high degree of necrosis. Furthermore, among 2422 genes that correlated with the degree of necrosis in GBMs, transcription factors known to drive the mesenchymal expression class were most closely related, including C/EBP-β, C/EBP-δ, STAT3, FOSL2, bHLHE40, and RUNX1. Non-mesenchymal GBMs in the TCGA data set were found to become more transcriptionally similar to the mesenchymal class with increasing levels of necrosis. In addition, high expression levels of the master mesenchymal factors C/EBP-β, C/EBP-δ, and STAT3 were associated with a poor prognosis. Strong, specific expression of C/EBP-β and C/EBP-δ by hypoxic, perinecrotic cells in GBM likely account for their tight association with necrosis and may be related to their poor prognosis. See related Commentary on page 1768 See related Commentary on page 1768 Glioblastoma (GBM) (World Health Organization, grade IV) is the most common and highest grade astrocytoma.1Louis D.N. Ohgaki H. Wiestler O.D. Cavenee W.K. WHO classification of tumours of the central nervous system.4th ed. Intl. Agency for Research, Lyon2007Google Scholar, 2CBTRUSCBTRUS statistical report: primary brain and central nervous system tumors in the United States in 2004–2006. Central Brain Tumor Registry of the United States, Hinsdale, IL2010Google Scholar Currently incurable, it has a mean survival that only slightly exceeds 1 year following standard surgical and adjuvant therapies.3Stupp R. Mason W.P. van den Bent M.J. Weller M. Fisher B. Taphoorn M.J. Belanger K. Brandes A.A. Marosi C. Bogdahn U. Curschmann J. Janzer R.C. Ludwin S.K. Gorlia T. Allgeier A. Lacombe D. Cairncross J.G. Eisenhauer E. Mirimanoff R.O. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma.N Engl J Med. 2005; 352: 987-996Crossref PubMed Scopus (12735) Google Scholar Analyses of large scale gene expression and genomic datasets have indicated that this disease represents multiple molecular subclasses, raising the possibility that future therapies could be directed at underlying class-specific mechanisms. Phillips et al4Phillips H.S. Kharbanda S. Chen R. Forrest W.F. Soriano R.H. Wu T.D. Misra A. Nigro J.M. Colman H. Soroceanu L. Williams P.M. Modrusan Z. Feuerstein B.G. Aldape K. Molecular subclasses of high-grade glioma predict prognosis, delineate a pattern of disease progression, and resemble stages in neurogenesis.Cancer Cell. 2006; 9: 157-173Abstract Full Text Full Text PDF PubMed Scopus (2114) Google Scholar and Verhaak et al5Verhaak R.G. Hoadley K.A. Purdom E. Wang V. Qi Y. Wilkerson M.D. Miller C.R. Ding L. Golub T. Mesirov J.P. Alexe G. Lawrence M. O'Kelly M. Tamayo P. Weir B.A. Gabriel S. Winckler W. Gupta S. Jakkula L. Feiler H.S. Hodgson J.G. James C.D. Sarkaria J.N. Brennan C. Kahn A. Spellman P.T. Wilson R.K. Speed T.P. Gray J.W. Meyerson M. Getz G. Perou C.M. Hayes D.N. Integrated genomic analysis identifies clinically relevant of glioblastoma by in and Cell. Full Text Full Text PDF PubMed Scopus Google Scholar have that of GBM gene expression in four transcriptional and alterations, including and of tumor and account for at transcriptional class of among The Cancer Genome Atlas (TCGA) proneural, neural, classical, and mesenchymal transcriptional and the in the transcriptional tumors with the mesenchymal R.G. Hoadley K.A. Purdom E. Wang V. Qi Y. Wilkerson M.D. Miller C.R. Ding L. Golub T. Mesirov J.P. Alexe G. Lawrence M. O'Kelly M. Tamayo P. Weir B.A. Gabriel S. Winckler W. Gupta S. Jakkula L. Feiler H.S. Hodgson J.G. James C.D. Sarkaria J.N. Brennan C. Kahn A. Spellman P.T. Wilson R.K. Speed T.P. Gray J.W. Meyerson M. Getz G. Perou C.M. Hayes D.N. Integrated genomic analysis identifies clinically relevant of glioblastoma by in and Cell. Full Text Full Text PDF PubMed Scopus Google Scholar, Genome Atlas genomic glioblastoma genes and PubMed Scopus Google Scholar, H. K. Phillips H.S. K. Verhaak R.G. Hoadley K.A. Hayes D.N. Perou C.M. Ding L. Wilson R.K. D. H. H. P. J. J.G. Aldape K. of a that a of Cell. Full Text Full Text PDF PubMed Scopus Google Scholar of the genomic in including and and and in multiple transcriptional that only partially the class-specific gene expression analysis of GBM expression used a to transcriptional and a set of transcription factors that the to the mesenchymal including C/EBP-β, C/EBP-δ, STAT3, FOSL2, bHLHE40, and RUNX1. C/EBP-β, C/EBP-δ, and STAT3 were found to be master transcriptional the expression of and for the of and the mesenchymal gene W.K. M.J. Colman H. A. Aldape K. A. A. The transcriptional for mesenchymal of brain PubMed Scopus Google Scholar of these master transcriptional were that of the tumor including tumor could both transcriptional and gene expression to expression the that related, to be molecular used to these we an and molecular analysis of factors to GBM transcriptional gene expression and of angiogenesis and necrosis in GBM molecular data and the digitized images frozen used for by the found that the mesenchymal class of GBM was enriched with samples a high degree of and that the expression of transcriptional of the mesenchymal C/EBP-β, C/EBP-δ, STAT3, FOSL2, bHLHE40, and were correlated with the of necrosis. GBMs more transcriptionally similar to the mesenchymal class with increasing levels of necrosis. GBM we that C/EBP-β and were by hypoxic, for the association of these factors with necrosis. that the high expression of C/EBP-β, C/EBP-δ, and STAT3 a poor that these may for of and related and data in at digitized images of GBM frozen were the TCGA section slides were and digitized at on an at the TCGA at the The frozen section slides were by for to that the the section and section were for molecular the used for molecular analysis by TCGA was immediately adjacent to the used to slides for this used these digitized images primary of data and necrosis on slides samples to was on slides samples to a of data on necrosis in GBM we used of GBMs that were by TCGA frozen section slides for these the necrosis was a of was only and was in analysis. were samples with the of of necrosis and angiogenesis were by and a on the features to J. Wang P.M. A. T. for in glioma PubMed Scopus Google Scholar The of were to adjacent the were necrosis angiogenesis were the were and of D.N. Ohgaki H. Wiestler O.D. Cavenee W.K. WHO classification of tumours of the central nervous system.4th ed. Intl. Agency for Research, Lyon2007Google Scholar, A. surgical a Scholar, of of PubMed Scopus Google Scholar In to the the including and were were The of necrosis and the of angiogenesis were a of by the of necrosis angiogenesis to the section were multiple slides to and class for TCGA were the TCGA the set of samples by Verhaak et al5Verhaak R.G. Hoadley K.A. Purdom E. Wang V. Qi Y. Wilkerson M.D. Miller C.R. Ding L. Golub T. Mesirov J.P. Alexe G. Lawrence M. O'Kelly M. Tamayo P. Weir B.A. Gabriel S. Winckler W. Gupta S. Jakkula L. Feiler H.S. Hodgson J.G. James C.D. Sarkaria J.N. Brennan C. Kahn A. Spellman P.T. Wilson R.K. Speed T.P. Gray J.W. Meyerson M. Getz G. Perou C.M. Hayes D.N. Integrated genomic analysis identifies clinically relevant of glioblastoma by in and Cell. Full Text Full Text PDF PubMed Scopus Google Scholar data to TCGA samples the for necrosis and angiogenesis were for association with transcriptional class with analysis of data were the GBM analysis at the Cancer data the TCGA was to was and samples gene expression data the was samples with multiple to expression with an expression of and a of were necrosis and angiogenesis were correlated with expression the the analysis of R. G. analysis of to the Scopus Google Scholar of C/EBP-β, C/EBP-δ, and STAT3 were by the was H. K. Phillips H.S. K. Verhaak R.G. Hoadley K.A. Hayes D.N. Perou C.M. Ding L. Wilson R.K. D. H. H. P. J. J.G. Aldape K. of a that a of Cell. Full Text Full Text PDF PubMed Scopus Google Scholar, B.A. T. The molecular is enriched in and survival among PubMed Scopus Google Scholar was to gene generated by analysis of analysis of necrosis and B.A. T. The molecular is enriched in and survival among PubMed Scopus Google Scholar and were were to and was by TCGA of for GBM samples with gene expression transcriptional class transcriptional class and the presence of was for C/EBP-β, C/EBP-δ, and STAT3 were with The mesenchymal was the classification to of to 2005; PubMed Scopus Google Scholar set of that mesenchymal samples were by by expression of mesenchymal and The mesenchymal was the expression of these of mesenchymal of to the mesenchymal was the by the of transcriptional and necrosis were GBM were of These GBMs with and contained of high-grade glioma with of and adjacent GBM were in and were on Y. C. Chen G. and expression in glioblastoma transcriptional PubMed Scopus Google Scholar, Y. R.O. and expression and by 2005; PubMed Scopus Google Scholar were and to by for were with directed and C/EBP-β C/EBP-δ and were the the the were with GBM have Y. C. 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M.J. Colman H. A. Aldape K. A. A. The transcriptional for mesenchymal of brain PubMed Scopus Google Scholar The master a was among the correlated genes at of the with of in TCGA among 2422 The Cancer Genome in a GBMs, The Cancer Genome gene expression and the of necrosis the mesenchymal expression class these into with necrosis and with of the 2422 genes correlated with necrosis significantly in the high necrosis including C/EBP-β and Because the master of the mesenchymal transcriptional class were data Phillips et al4Phillips H.S. Kharbanda S. Chen R. Forrest W.F. Soriano R.H. Wu T.D. Misra A. Nigro J.M. Colman H. Soroceanu L. Williams P.M. Modrusan Z. Feuerstein B.G. Aldape K. Molecular subclasses of high-grade glioma predict prognosis, delineate a pattern of disease progression, and resemble stages in neurogenesis.Cancer Cell. 2006; 9: 157-173Abstract Full Text Full Text PDF PubMed Scopus (2114) Google Scholar, we these transcription factors were also enriched the mesenchymal class by TCGA R.G. Hoadley K.A. Purdom E. Wang V. Qi Y. Wilkerson M.D. Miller C.R. Ding L. Golub T. Mesirov J.P. Alexe G. Lawrence M. O'Kelly M. Tamayo P. Weir B.A. Gabriel S. Winckler W. Gupta S. Jakkula L. Feiler H.S. Hodgson J.G. James C.D. Sarkaria J.N. Brennan C. Kahn A. Spellman P.T. Wilson R.K. Speed T.P. Gray J.W. Meyerson M. Getz G. Perou C.M. Hayes D.N. Integrated genomic analysis identifies clinically relevant of glioblastoma by in and Cell. Full Text Full Text PDF PubMed Scopus Google Scholar found that C/EBP-β, C/EBP-δ, STAT3, FOSL2, and were significantly mesenchymal tumors to In of C/EBP-β was most by FOSL2, bHLHE40, C/EBP-δ, and STAT3 The was also significantly in the mesenchymal in of transcription expression among expression we that C/EBP-δ, STAT3, and similar expression in and mesenchymal tumors of the in and expression of C/EBP-δ, STAT3, and was mesenchymal and in a The expression of C/EBP-δ, STAT3, and was mesenchymal and that were significantly associated with the of necrosis were to to enriched in gene associated with necrosis analysis of genes significantly enriched associated with and including system and analysis of for angiogenesis only significantly correlated of were mesenchymal master at The of the necrosis and angiogenesis correlated gene contained significantly correlated including the correlated gene the of on genes to the of the used for that the of angiogenesis represents only a of the for the large of angiogenesis and gene expression were most likely to in the and also a analysis on genes in high and necrosis mesenchymal this significantly enriched associated with and including and E. Y. glioblastoma cells in and in Google Scholar, B. and the in glioma and 2005; PubMed Scopus Google Scholar expression of master of the mesenchymal was correlated with we used TCGA data to the survival of with high expression to with expression of C/EBP-β, C/EBP-δ, and STAT3 the of gene their GBMs with high expression of C/EBP-β were associated with a significantly survival with expression expression of C/EBP-δ a survival high expression of STAT3 was significantly associated with a survival The of high C/EBP-β, C/EBP-δ, and STAT3 was associated with a survival to that expression Molecular by Verhaak et al5Verhaak R.G. Hoadley K.A. Purdom E. Wang V. Qi Y. Wilkerson M.D. Miller C.R. Ding L. Golub T. Mesirov J.P. Alexe G. Lawrence M. O'Kelly M. Tamayo P. Weir B.A. Gabriel S. Winckler W. Gupta S. Jakkula L. Feiler H.S. Hodgson J.G. James C.D. Sarkaria J.N. Brennan C. Kahn A. Spellman P.T. Wilson R.K. Speed T.P. Gray J.W. Meyerson M. Getz G. Perou C.M. Hayes D.N. Integrated genomic analysis identifies clinically relevant of glioblastoma by in and Cell. 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M.J. Colman H. A. Aldape K. A. A. The transcriptional for mesenchymal of brain PubMed Scopus Google Scholar be because C/EBP-β, C/EBP-δ, and STAT3 by a associated with necrosis and with the of L. in PubMed Scopus Google Scholar, S.K. J. Y. C. G. J. a in the transcription gene expression in to PubMed Scopus Google Scholar, H. D. R. in and a for 9: PubMed Scopus Google Scholar the set of TCGA GBMs by a of TCGA and for for molecular we an of GBMs with the transcriptional class in the mesenchymal we the gene expression of C/EBP-β, C/EBP-δ, STAT3, FOSL2, bHLHE40, and in with to we the pattern and degree of in GBMs, related to necrosis and to the expression of C/EBP-β, C/EBP-δ, and STAT3, we on to high grade glioma with necrosis and and adjacent was used to the of the tumor and to the of transcription expression in this The of GBM samples to the large of cells were in were brain tumor and in cells necrosis were enriched with with A.A. M. C. B. in glioblastoma hypoxic, and by an PubMed Scopus Google Scholar The of necrosis the of these GBMs to found that the expression of STAT3 and was in the expression of both C/EBP-δ and C/EBP-β was was a of necrosis and these GBM samples C/EBP-β, C/EBP-δ, and STAT3 were by these only a of cells GBM samples and only a with the of necrosis. In of C/EBP-β, C/EBP-δ, and we a pattern of expression of C/EBP-β and C/EBP-δ that correlated with the presence and degree of necrosis C/EBP-β and C/EBP-δ were to the cells that necrosis in Y. necrosis in a that and 2006; PubMed Scopus Google Scholar These cells the necrosis and factors and and Y. 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Wilkerson M.D. Miller C.R. Ding L. Golub T. Mesirov J.P. Alexe G. Lawrence M. O'Kelly M. Tamayo P. Weir B.A. Gabriel S. Winckler W. Gupta S. Jakkula L. Feiler H.S. Hodgson J.G. James C.D. Sarkaria J.N. Brennan C. Kahn A. Spellman P.T. Wilson R.K. Speed T.P. Gray J.W. Meyerson M. Getz G. Perou C.M. Hayes D.N. Integrated genomic analysis identifies clinically relevant of glioblastoma by in and Cell. Full Text Full Text PDF PubMed Scopus Google Scholar The mesenchymal transcriptional class was enriched with tumor samples that contained levels of necrosis in the proneural, neural, and In a transcriptional class of GBM associated with levels of necrosis was that among the their expression and the of necrosis transcription factors that were of the mesenchymal C/EBP-β, C/EBP-δ, STAT3, FOSL2, and W.K. M.J. Colman H. A. Aldape K. A. A. The transcriptional for mesenchymal of brain PubMed Scopus Google Scholar a analysis and gene expression data Phillips et al4Phillips H.S. Kharbanda S. Chen R. Forrest W.F. Soriano R.H. Wu T.D. Misra A. Nigro J.M. Colman H. Soroceanu L. Williams P.M. Modrusan Z. Feuerstein B.G. Aldape K. Molecular subclasses of high-grade glioma predict prognosis, delineate a pattern of disease progression, and resemble stages in neurogenesis.Cancer Cell. 2006; 9: 157-173Abstract Full Text Full Text PDF PubMed Scopus (2114) Google Scholar, these factors were found to account for of the genes the mesenchymal gene H.S. Kharbanda S. Chen R. Forrest W.F. Soriano R.H. Wu T.D. Misra A. Nigro J.M. Colman H. Soroceanu L. Williams P.M. Modrusan Z. Feuerstein B.G. Aldape K. Molecular subclasses of high-grade glioma predict prognosis, delineate a pattern of disease progression, and resemble stages in neurogenesis.Cancer Cell. 2006; 9: 157-173Abstract Full Text Full Text PDF PubMed Scopus (2114) Google Scholar, W.K. M.J. Colman H. A. Aldape K. A. A. The transcriptional for mesenchymal of brain PubMed Scopus Google Scholar with their in the transcriptional of the mesenchymal TCGA data that C/EBP-β, C/EBP-δ, STAT3, FOSL2, and were in the mesenchymal GBMs to the for the of GBM samples into specific expression likely multiple is that and alterations, including and alterations, have an on the transcriptional GBMs with the proneural, with enriched in the mesenchymal R.G. Hoadley K.A. Purdom E. Wang V. Qi Y. Wilkerson M.D. Miller C.R. Ding L. Golub T. Mesirov J.P. Alexe G. Lawrence M. O'Kelly M. Tamayo P. Weir B.A. Gabriel S. Winckler W. Gupta S. Jakkula L. Feiler H.S. Hodgson J.G. James C.D. Sarkaria J.N. Brennan C. Kahn A. Spellman P.T. Wilson R.K. Speed T.P. Gray J.W. Meyerson M. Getz G. Perou C.M. Hayes D.N. Integrated genomic analysis identifies clinically relevant of glioblastoma by in and Cell. Full Text Full Text PDF PubMed Scopus Google Scholar, H. K. Phillips H.S. K. Verhaak R.G. Hoadley K.A. Hayes D.N. Perou C.M. Ding L. Wilson R.K. D. H. H. P. J. J.G. Aldape K. of a that a of Cell. Full Text Full Text PDF PubMed Scopus Google Scholar tumors with in and found in multiple transcriptional an association these common and the of necrosis in GBM that the of high necrosis and mesenchymal The mesenchymal GBMs with the highest levels of necrosis a similar of in these genes with necrosis in transcriptional These that similar be associated with transcriptional and that associated with necrosis and may transcriptional class the transcription factors by et W.K. M.J. Colman H. A. Aldape K. A. A. The transcriptional for mesenchymal of brain PubMed Scopus Google Scholar, of the mesenchymal it was by in and in that C/EBP-β, C/EBP-δ, and STAT3 were master transcriptional and the in a These were that may be to tumor Because C/EBP-β, C/EBP-δ, and STAT3 known for their in we their with necrosis in GBM was to expression by to in with L. in PubMed Scopus Google Scholar, S.K. J. Y. C. G. J. a in the transcription gene expression in to PubMed Scopus Google Scholar, H. D. R. in and a for 9: PubMed Scopus Google Scholar In analysis of TCGA GBMs by a of we found association the degree of and the mesenchymal transcriptional was a degree of and the expression of C/EBP-β, C/EBP-δ, and In a of expression of these transcription this for a of cells in GBM with the of cells the expression of C/EBP-β, C/EBP-δ, and STAT3 by may to the mesenchymal most likely in a In to may be of cells that could to the mesenchymal and of also the necrosis that in GBM could account for the of mesenchymal transcription and associated features that in the microenvironment to GBM and associated with Y. necrosis in a that and 2006; PubMed Scopus Google Scholar, B. and the in glioma and 2005; PubMed Scopus Google Scholar, M. J.G. J.M. R.C. K.A. in glioblastoma quantified with with to and Cancer PubMed Scopus Google Scholar The of cells that in GBM hypoxic, and factors including and to an that tumor Y. necrosis in a that and 2006; PubMed Scopus Google Scholar, A.A. M. C. B. in glioblastoma hypoxic, and by an PubMed Scopus Google Scholar, The of and in and 2005; PubMed Scopus Google Scholar that the expression of C/EBP-β was and specific these cells in GBM C/EBP-δ was also in was cells that were necrosis only expression of C/EBP-β and this it be that C/EBP-β and C/EBP-δ gene and expression with the degree of necrosis in GBMs, in analysis. STAT3 expression a association with necrosis in GBM and with necrosis by gene expression analysis could be explained the gene expression and degree of it could be that the transcriptional to tumors that more to that the of necrosis a in transcriptional S. K. W. R. of necrosis associated genes in glioblastoma by Cancer PubMed Scopus Google Scholar it more likely that necrosis the transcriptional of the master transcriptional C/EBP-β and C/EBP-δ, the of in the mesenchymal were found to be by perinecrotic cells in GBM and C/EBP-β was by in that the of necrosis to of these the C/EBP-β was the most associated with the mesenchymal transcription class and with the of necrosis the mesenchymal GBM C/EBP-β also the most specific expression in cells in GBM samples and was in C/EBP-δ was by in may that in perinecrotic cells is to high these data that C/EBP-β may be most for the tight association necrosis and the mesenchymal gene that GBM transcriptional by the of necrosis and could a of tumors GBMs were to be more transcriptionally similar to the mesenchymal class with increasing levels of that may be transcriptional that on necrosis and that transcriptional may be found the GBM and on the degree of necrosis the These and to be therapies directed specific molecular in the their to transcriptional class it is that these master transcriptional of tumor the TCGA and including transcriptional GBMs with high expression of C/EBP-β, C/EBP-δ, and STAT3 with These data that these master their may be The and for their with the and the of Cancer including and for their with and with with with with with with with with in and of Commentary the by et the association of mesenchymal glioblastoma with necrosis and poor prognosis, for PDF
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