The tumor microenvironment strongly impacts master transcriptional regulators and gene expression class of glioblastoma

Lee A D Cooper; David A. Gutman; Candace Chisolm; Christina Appin; Jun Kong; Yuan Rong; Tahsin Kurc; Erwin G. Van Meir; Joel H. Saltz; Carlos S. Moreno; Daniel J. Brat

doi:10.1016/j.ajpath.2012.01.040

The tumor microenvironment strongly impacts master transcriptional regulators and gene expression class of glioblastoma

Lee A D Cooper, David A. Gutman, Candace Chisolm, Christina Appin, Jun Kong, Yuan Rong, Tahsin Kurc, Erwin G. Van Meir, Joel H. Saltz, Carlos S. Moreno, Daniel J. Brat^*

^*Corresponding author for this work

Pathology

Research output: Contribution to journal › Article › peer-review

185 Scopus citations

Abstract

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.

Original language	English (US)
Pages (from-to)	2108-2119
Number of pages	12
Journal	American Journal of Pathology
Volume	180
Issue number	5
DOIs	https://doi.org/10.1016/j.ajpath.2012.01.040
State	Published - May 2012

Funding

This work was supported by the United States Public Health Service, NIH grants CA149107 (D.J.B.), LM011119 (J.H.S.), CA86335 and CA116804 (E.G.V.M.), CA138292 ( Winship Cancer Center Support Grant), the National Cancer Institute's Cancer Bioinformatics Grid (CaBIG), In Silico Research Center of Excellence Contract HHSN261200800001E and NO1-CO-12400 (T.K., E.G.V.M., S.H.S., C.S.M., D.J.B.), the Georgia Research Alliance (J.H.S.), and the Georgia Cancer Coalition (J.H.S., D.J.B.).

ASJC Scopus subject areas

Pathology and Forensic Medicine

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.ajpath.2012.01.040

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Cooper, 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. (2012). The tumor microenvironment strongly impacts master transcriptional regulators and gene expression class of glioblastoma. American Journal of Pathology, 180(5), 2108-2119. https://doi.org/10.1016/j.ajpath.2012.01.040

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title = "The tumor microenvironment strongly impacts master transcriptional regulators and gene expression class of glioblastoma",

abstract = "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.",

author = "Cooper, {Lee A D} and Gutman, {David A.} and Candace Chisolm and Christina Appin and Jun Kong and Yuan Rong and Tahsin Kurc and {Van Meir}, {Erwin G.} and Saltz, {Joel H.} and Moreno, {Carlos S.} and Brat, {Daniel J.}",

note = "Funding Information: This work was supported by the United States Public Health Service, NIH grants CA149107 (D.J.B.), LM011119 (J.H.S.), CA86335 and CA116804 (E.G.V.M.), CA138292 ( Winship Cancer Center Support Grant), the National Cancer Institute's Cancer Bioinformatics Grid (CaBIG), In Silico Research Center of Excellence Contract HHSN261200800001E and NO1-CO-12400 (T.K., E.G.V.M., S.H.S., C.S.M., D.J.B.), the Georgia Research Alliance (J.H.S.), and the Georgia Cancer Coalition (J.H.S., D.J.B.). ",

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T1 - The tumor microenvironment strongly impacts master transcriptional regulators and gene expression class of glioblastoma

AU - Cooper, Lee A D

AU - Gutman, David A.

AU - Chisolm, Candace

AU - Appin, Christina

AU - Kong, Jun

AU - Rong, Yuan

AU - Kurc, Tahsin

AU - Van Meir, Erwin G.

AU - Saltz, Joel H.

AU - Moreno, Carlos S.

AU - Brat, Daniel J.

N1 - Funding Information: This work was supported by the United States Public Health Service, NIH grants CA149107 (D.J.B.), LM011119 (J.H.S.), CA86335 and CA116804 (E.G.V.M.), CA138292 ( Winship Cancer Center Support Grant), the National Cancer Institute's Cancer Bioinformatics Grid (CaBIG), In Silico Research Center of Excellence Contract HHSN261200800001E and NO1-CO-12400 (T.K., E.G.V.M., S.H.S., C.S.M., D.J.B.), the Georgia Research Alliance (J.H.S.), and the Georgia Cancer Coalition (J.H.S., D.J.B.).

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N2 - 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.

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The tumor microenvironment strongly impacts master transcriptional regulators and gene expression class of glioblastoma

Abstract

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ASJC Scopus subject areas

UN SDGs

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