Year: 2012
Type: article
Abstract: See related article on page 2108 See related article on page 2108 Glioblastomas (GBMs) are the most common malignant brain tumors, but they are currently incurable. It is hoped that targeted therapies may prove effective in improving survival. Indeed, efforts to integrate multimodal molecular and clinical data for brain tumors have begun to yield a clearer picture of these aggressive neoplasms. The Cancer Genome Atlas (TCGA)1McLendon R. Friedman A. Bigner D. Van Meir E.G. Brat D.J. Mastrogianakis G.M. Cancer Genome Atlas Research Network: Comprehensive genomic characterization defines human glioblastoma genes and core pathways.Nature. 2008; 455: 1061-1068Crossref PubMed Scopus (5895) Google Scholar and the Repository of Molecular Brain Neoplasia Data (REMBRANDT)2Madhavan S. Zenklusen J.C. Kotliarov Y. Sahni H. Fine H.A. Buetow K. Rembrandt: helping personalized medicine become a reality through integrative translational research.Mol Cancer Res. 2009; 7: 157-167Crossref PubMed Scopus (319) Google Scholar both support numerous data sets for mRNA and miRNA expression, DNA copy number alterations, sequencing data, and both magnetic resonance and histological images. Many of the molecular underpinnings of GBM have been identified, the most abundant mutations have been catalogued, and perturbed signaling pathways have been elucidated.1McLendon R. Friedman A. Bigner D. Van Meir E.G. Brat D.J. Mastrogianakis G.M. Cancer Genome Atlas Research Network: Comprehensive genomic characterization defines human glioblastoma genes and core pathways.Nature. 2008; 455: 1061-1068Crossref PubMed Scopus (5895) Google Scholar Mutations in isocitrate dehydrogenase 1 and 2 have been identified, and a relationship to secondary GBM has been established.3Yan H. Parsons D.W. Jin G. McLendon R. Rasheed B.A. Yuan W. Kos I. Batinic-Haberle I. Jones S. Riggins G.J. Friedman H. Friedman A. Reardon D. Herndon J. Kinzler K.W. Velculescu V.E. Vogelstein B. Bigner D.D. IDH1 and IDH2 mutations in gliomas.N Engl J Med. 2009; 360: 765-773Crossref PubMed Scopus (4329) Google Scholar, 4Verhaak 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. 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. 2010; 17: 98-110Abstract Full Text Full Text PDF PubMed Scopus (5091) Google Scholar A group of tumors with a CpG island methylator phenotype has been described, portending an improved prognosis.5Noushmehr H. Weisenberger D.J. Diefes K. Phillips H.S. Pujara K. Berman B.P. Pan F. Pelloski C.E. Sulman E.P. Bhat K.P. Verhaak R.G. Hoadley K.A. Hayes D.N. Perou C.M. Schmidt H.K. Ding L. Wilson R.K. Van Den Berg D. Shen H. Bengtsson H. Neuvial P. Cope L.M. Buckley J. Herman J.G. Baylin S.B. Laird P.W. Aldape K. Cancer Genome Atlas Research Network: Identification of a CpG island methylator phenotype that defines a distinct subgroup of glioma.Cancer Cell. 2010; 17: 510-522Abstract Full Text Full Text PDF PubMed Scopus (1809) Google Scholar These efforts and others have also resulted in the identification of three or four transcriptional classes of GBM.4Verhaak 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. 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. 2010; 17: 98-110Abstract Full Text Full Text PDF PubMed Scopus (5091) Google Scholar, 6Phillips 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 (2338) Google Scholar Common to all of the major molecular classification schemes for GBM is a group that characteristically shows increased expression of mesenchymal genes. This mesenchymal expression signature has been associated with reduced survival and aggressive behavior.6Phillips 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 (2338) Google Scholar Despite these new insights into the biology of GBM, and the promise of more tailored therapy on the horizon, the diagnosis of GBM is still made using a more fundamental technique: microscopic examination of H&E-stained slides. Over the years, several different histopathological grading systems for GBM and other astrocytomas have been used, including the Kernahan system, the St. Anne/Mayo system, and the now current World Health Organization (WHO) system.7Kleihues P. Soylemezoglu F. Schäuble B. Scheithauer B.W. Burger P.C. Histopathology, classification, and grading of gliomas.Glia. 1995; 15: 211-221Crossref PubMed Scopus (317) Google Scholar, 8Louis D.N. Ohgaki H. Wiestler O.D. Cavenee W.K. WHO Classification of Tumours of the Central Nervous System. ed 4. IARC Press, Lyon2007Google Scholar A consistent feature of all these diagnostic schemata is the inclusion of necrosis and vascular proliferation, two elements of the tumor microenvironment, as indicators of poor prognosis. The reduction in patient survival associated with these features has withstood the test of time and multiple confirmatory studies (reviewed by Brat et al9Brat D.J. Prayson R.A. Ryken T.C. Olson J.J. Diagnosis of malignant glioma: role of neuropathology.J Neurooncol. 2008; 89: 287-311Crossref PubMed Scopus (75) Google Scholar). In this issue of The American Journal of Pathology, Cooper et al10Cooper L.A.D. Gutman D.A. Chisolm C. Appin C. Kong J. Rong Y. Kurc T. Van Meir E.G. Saltz J.H. Moreno C.S. Brat D.J. The tumor microenvironment strongly impacts master transcriptional regulators and gene expression class of glioblastoma.Am J Pathol. 2012; 180: 2108-2119Abstract Full Text Full Text PDF PubMed Scopus (168) Google Scholar report their correlation of histopathological features of the tumor microenvironment with gene expression patterns developed by the large multimodality genomics efforts. They identify an intimate association between necrosis in GBM and the mesenchymal transcriptional class. The degree of necrosis demonstrated a close association with genes that define mesenchymal class, including master regulators such as STAT3 and C/EBP-β.11Carro M.S. Lim W.K. Alvarez M.J. Bollo R.J. Zhao X. Snyder E.Y. Sulman E.P. Anne S.L. Doetsch F. Colman H. Lasorella A. Aldape K. Califano A. Iavarone A. The transcriptional network for mesenchymal transformation of brain tumours.Nature. 2010; 463: 318-325Crossref PubMed Scopus (925) Google Scholar Perhaps their most interesting finding was that increasing mesenchymal expression signature among nonmesenchymal-class tumors correlated with the extent of necrosis (Figure 1). This highlights the important contribution of the tumor microenvironment in dictating mRNA transcription and represents an important first step in integrating microscopic features and gene expression patterns in a more quantitative and sophisticated way. The microscopic analysis of tumor morphology is not new; in fact, it represents the basis of most studies in anatomical pathology. Because of relatively recent technological advancements, however, quantitative morphometry has become increasingly sophisticated. Improvements in imaging technology, including the ability to scan slides and store images with relative speed, increases in storage capacity, and production of powerful software platforms such as NIH Image and ImageJ have facilitated robust quantitative analysis of histological images on morphological grounds. Technology in molecular biology allowing for multimodal data acquisition of mRNA expression, genetics, and epigenetics has progressed even more rapidly. The field of glioma biology benefited from GBM being selected early as one of the tumors to be added to large public data sets such as the TCGA, which include not only expression profiles but also scanned slide and radiographic images for future correlation with molecular data. Computer-based image analysis has been used previously to evaluate the TCGA data set. For instance, Cooper and colleagues12Kong J. Cooper L. Moreno C. Wang F. Kurc T. Saltz J. Brat D. In silico analysis of nuclei in glioblastoma using large-scale microscopy images improves prediction of treatment response.Conf Proc IEEE Eng Med Biol Soc. 2011; 2011: 87-90PubMed Google Scholar, 13Cooper L.A. Kong J. Wang F. Kurc T. Moreno C.S. Brat D.J. Saltz J.H. Morphological Signatures and Genomic Correlates in Glioblastoma.Proc IEEE Int Symp Biomed Imaging. 2011; 1624 earlier used nuclear segmentation analysis to cluster TCGA tumors into three morphometric classes. Similar to clustering by transcriptional classes, which was reported by Verhaak et al,4Verhaak 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. 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. 2010; 17: 98-110Abstract Full Text Full Text PDF PubMed Scopus (5091) Google Scholar morphometric clustering correlated with specific signaling pathways and survival profiles.12Kong J. Cooper L. Moreno C. Wang F. Kurc T. Saltz J. Brat D. In silico analysis of nuclei in glioblastoma using large-scale microscopy images improves prediction of treatment response.Conf Proc IEEE Eng Med Biol Soc. 2011; 2011: 87-90PubMed Google Scholar, 13Cooper L.A. Kong J. Wang F. Kurc T. Moreno C.S. Brat D.J. Saltz J.H. Morphological Signatures and Genomic Correlates in Glioblastoma.Proc IEEE Int Symp Biomed Imaging. 2011; 1624 An analogous approach, using distinct criteria, generated five morphometric clusters from the TCGA data set and was predictive of therapeutic outcome.14Chang H. Fontenay G.V. Han J. Cong G. Baehner F.L. Gray J.W. Spellman P.T. Parvin B. Morphometic analysis of TCGA glioblastoma multiforme.BMC Bioinformatics. 2011; 12: 484Crossref PubMed Scopus (39) Google Scholar These early results are encouraging, but thus far morphometric clustering has not shown the tight association with specific molecular aberrations that has been observed with transcriptional clustering. The present contribution by Cooper et al10Cooper L.A.D. Gutman D.A. Chisolm C. Appin C. Kong J. Rong Y. Kurc T. Van Meir E.G. Saltz J.H. Moreno C.S. Brat D.J. The tumor microenvironment strongly impacts master transcriptional regulators and gene expression class of glioblastoma.Am J Pathol. 2012; 180: 2108-2119Abstract Full Text Full Text PDF PubMed Scopus (168) Google Scholar differs from previous efforts in that, rather than correlating intrinsic features of single cells (most often nuclear details) with TCGA data, they examined broader aspects of the tumor microenvironment, evaluating three components: necrosis, angiogenesis, and macrophage infiltration. Necrosis appeared to have the strongest relationship to the previously defined transcriptional classes, and in particular to the mesenchymal subgroup. Necrosis is a strong predictor of behavior in malignant glioma.9Brat D.J. Prayson R.A. Ryken T.C. Olson J.J. Diagnosis of malignant glioma: role of neuropathology.J Neurooncol. 2008; 89: 287-311Crossref PubMed Scopus (75) Google Scholar Intratumoral necrosis likely results from multiple mechanisms. Focal necrosis occurs when the energy requirements of the highly proliferative tumor cells outpace their own energy supply. However, a more complex mechanism has been suggested for large areas of necrosis within GBM. These have been attributed to vascular thrombosis, which is often identified within tumors and seen in a high proportion of pseudopalisades in GBM.15Brat D.J. Castellano-Sanchez A.A. Hunter S.B. Pecot M. Cohen C. Hammond E.H. Devi S.N. Kaur B. Van Meir E.G. Pseudopalisades in glioblastoma are hypoxic, express extracellular matrix proteases, and are formed by an actively migrating cell population.Cancer Res. 2004; 64: 920-927Crossref PubMed Scopus (352) Google Scholar Thrombosis of vessels may be related to a number of derangements in the coagulation cascade, but has specifically been attributed to the induction of tissue factor by tumor cells.16Brat D.J. Van Meir E.G. Vaso-occlusive and prothrombotic mechanisms associated with tumor hypoxia, necrosis, and accelerated growth in glioblastoma.Lab Invest. 2004; 84: 397-405Crossref PubMed Scopus (246) Google Scholar Tissue factor may promote coagulation in intratumoral vessels by directly inciting the coagulation cascade.16Brat D.J. Van Meir E.G. Vaso-occlusive and prothrombotic mechanisms associated with tumor hypoxia, necrosis, and accelerated growth in glioblastoma.Lab Invest. 2004; 84: 397-405Crossref PubMed Scopus (246) Google Scholar Finally, as antiangiogenic therapies such as bevacizumab are increasingly used in malignant gliomas, we will likely encounter more therapeutically induced hypoxia and necrosis. How necrosis modulates gene expression is an area of active investigation. It may involve the induction of hypoxia-inducible transcription factors (HIF1-α and HIF2-α), the release of growth factors by dying cells, or eliciting necrosis-associated inflammation. HIF transcription factors are concentrated around necrotic regions in GBM, and they seem to promote a phenotype in tumor Z. S. Wu Wang H. C. S. Y. J. McLendon J.N. factors of glioma Cell. 2009; 15: Full Text Full Text PDF PubMed Scopus Google Scholar, A. V. W. increases the expression of and in glioblastoma J Pathol. 2010; Full Text Full Text PDF PubMed Scopus Google Scholar et Z. S. Wu Wang H. C. S. Y. J. McLendon J.N. factors of glioma Cell. 2009; 15: Full Text Full Text PDF PubMed Scopus Google Scholar demonstrated that was in brain tumor cells in to hypoxia, and of in and in group that hypoxia increased the expression of cell and increased the of GBM in a A. V. W. increases the expression of and in glioblastoma J Pathol. 2010; Full Text Full Text PDF PubMed Scopus Google Scholar The reported by Cooper et al10Cooper L.A.D. Gutman D.A. Chisolm C. Appin C. Kong J. Rong Y. Kurc T. Van Meir E.G. Saltz J.H. Moreno C.S. Brat D.J. The tumor microenvironment strongly impacts master transcriptional regulators and gene expression class of glioblastoma.Am J Pathol. 2012; 180: 2108-2119Abstract Full Text Full Text PDF PubMed Scopus (168) Google Scholar thus a between necrosis, mesenchymal gene expression and the It be to HIF directly the transcription of mesenchymal genes in to that will a approach, or DNA sequencing however, the data that mesenchymal genes are directly by For instance, the genes and are of (reviewed by et B. and in growth and 2011; 12: Google and are among the genes that define the mesenchymal transcriptional 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. 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. 2010; 17: 98-110Abstract Full Text Full Text PDF PubMed Scopus (5091) Google Scholar is association of the master regulators of the mesenchymal class and HIF in however, has been shown to be a of the M. F. A. T. F. T. A. T. T. K. K. H. and to with as the and as the in 2012; PubMed Scopus Google Scholar The present report the that be by HIF in glioma as For instance, the demonstrated that is highly in the cells in and is induced in hypoxia in L.A.D. Gutman D.A. Chisolm C. Appin C. Kong J. Rong Y. Kurc T. Van Meir E.G. Saltz J.H. Moreno C.S. Brat D.J. The tumor microenvironment strongly impacts master transcriptional regulators and gene expression class of glioblastoma.Am J Pathol. 2012; 180: 2108-2119Abstract Full Text Full Text PDF PubMed Scopus (168) Google Scholar The of glioma cells around areas of necrosis has been reported previously for D.J. Castellano-Sanchez A.A. Hunter S.B. Pecot M. Cohen C. Hammond E.H. Devi S.N. Kaur B. Van Meir E.G. Pseudopalisades in glioblastoma are hypoxic, express extracellular matrix proteases, and are formed by an actively migrating cell population.Cancer Res. 2004; 64: 920-927Crossref PubMed Scopus (352) Google Scholar master regulators of the mesenchymal class, such as may also HIF For instance, it was reported that a that clusters in the mesenchymal transcriptional class, the of S. J.N. R.G. The 1 tumor cell growth by and of in and in Res. 2010; PubMed Scopus Google Scholar STAT3 was shown in to a transcriptional complex with and of STAT3 the ability of to such as M.J. J. L.M. and are of a transcriptional complex that expression of in and PubMed Scopus Google Scholar, J. S. G. M. S. T. J. H. R. H. both and expression induced by multiple growth signaling PubMed Scopus Google Scholar It be interesting to STAT3 of HIF in glioma for such as The by Cooper et al10Cooper L.A.D. Gutman D.A. Chisolm C. Appin C. Kong J. Rong Y. Kurc T. Van Meir E.G. Saltz J.H. Moreno C.S. Brat D.J. The tumor microenvironment strongly impacts master transcriptional regulators and gene expression class of glioblastoma.Am J Pathol. 2012; 180: 2108-2119Abstract Full Text Full Text PDF PubMed Scopus (168) Google Scholar have For instance, the relationship between necrosis and the mesenchymal gene expression was other of the microenvironment as and examined This is to of the data set. In the of angiogenesis, histopathological analysis of the only the and The analysis of was It has been previously that the mesenchymal class of 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. 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. 2010; 17: 98-110Abstract Full Text Full Text PDF PubMed Scopus (5091) Google Scholar and to be associated with increased necrosis in the analysis of the data set. Cooper et al10Cooper L.A.D. Gutman D.A. Chisolm C. Appin C. Kong J. Rong Y. Kurc T. Van Meir E.G. Saltz J.H. Moreno C.S. Brat D.J. The tumor microenvironment strongly impacts master transcriptional regulators and gene expression class of glioblastoma.Am J Pathol. 2012; 180: 2108-2119Abstract Full Text Full Text PDF PubMed Scopus (168) Google Scholar evaluate of and their relationship to gene expression, the on a for and rather than the more used to necrosis. a of other cells was not specific a contribution of cells or vessels to the mesenchymal transcriptional class has not been Perhaps future to the TCGA will include analysis of vessels and cells, to for more robust of the tumor The present several important to of glioma For instance, it will be to more and the microenvironment within transcriptional classes. It is that cluster within specific transcriptional class, such as IDH1 mutations in the group and 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. 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. 2010; 17: 98-110Abstract Full Text Full Text PDF PubMed Scopus (5091) Google Scholar directly mesenchymal gene promote the mesenchymal transcriptional class through a complex with HIF or by a tumor through of tumor or vascular may also be from the of tumors that not the such as mesenchymal tumors with or necrosis. It be to other of such as the mesenchymal gene signature in tumors with or of necrosis. more will have to be as transcriptional classes become into clinical Cooper et al10Cooper L.A.D. Gutman D.A. Chisolm C. Appin C. Kong J. Rong Y. Kurc T. Van Meir E.G. Saltz J.H. Moreno C.S. Brat D.J. The tumor microenvironment strongly impacts master transcriptional regulators and gene expression class of glioblastoma.Am J Pathol. 2012; 180: 2108-2119Abstract Full Text Full Text PDF PubMed Scopus (168) Google Scholar report that tumors become more mesenchymal with increasing necrosis. This finding a degree of between transcriptional classes. It will be important to in transcriptional class within this occurs to a in the core of a tumor may yield a mesenchymal more yield an transcriptional class. clinical in which within transcriptional class may prove important is in the of tumor and transcriptional class has not been identified between the of and tumors previously 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. 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. 2010; 17: 98-110Abstract Full Text Full Text PDF PubMed Scopus (5091) Google Scholar this finding will in data The of such as which specifically angiogenesis, may also a mesenchymal class by increasing intratumoral The of molecular into new therapeutic thus to more The and of American Journal of Cancer Genome Atlas has generated gene expression data that glioblastoma into four transcriptional and Because transcriptional class is only by genomic alterations, we that the tumor microenvironment may also have an In this we on necrosis and their is both and These features in histological images of TCGA GBM slides that to used for molecular PDF
Source: American Journal Of Pathology
Authors: Brent A. Orr, Charles G. Eberhart
Institution: Johns Hopkins University
Language: English
Subfield: Genetics
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Estimated APC paid: $2,800
Awards: G261601865, G4001129516, G4956386925
OpenAlex ID: W80258794