Multiscale, multimodal analysis of tumor heterogeneity in IDH1 mutant vs wild-type diffuse gliomas.
Glioma is recognized to be a highly heterogeneous CNS malignancy, whose diverse cellular composition and cellular interactions have not been well characterized. To gain new clinical- and biological-insights into the genetically-bifurcated IDH1 mutant (mt) vs wildtype (wt) forms of glioma, we integra...
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doaj-1e809134b36d47c88e669627661aa0b72021-03-04T11:20:04ZengPublic Library of Science (PLoS)PLoS ONE1932-62032019-01-011412e021972410.1371/journal.pone.0219724Multiscale, multimodal analysis of tumor heterogeneity in IDH1 mutant vs wild-type diffuse gliomas.Michael E BerensAnup SoodJill S Barnholtz-SloanJohn F GrafSanghee ChoSeungchan KimJeffrey KieferSara A ByronRebecca F HalperinSara NasserJonathan AdkinsLori CuyuganKaren DevineQuinn OstromMarta CouceLeo WolanskyElizabeth McDonoughShannon SchybergSean DinnAndrew E SloanMichael PradosJoanna J PhillipsSarah J NelsonWinnie S LiangYousef Al-KofahiMirabela RusuMaria I ZavodszkyFiona GintyGlioma is recognized to be a highly heterogeneous CNS malignancy, whose diverse cellular composition and cellular interactions have not been well characterized. To gain new clinical- and biological-insights into the genetically-bifurcated IDH1 mutant (mt) vs wildtype (wt) forms of glioma, we integrated data from protein, genomic and MR imaging from 20 treatment-naïve glioma cases and 16 recurrent GBM cases. Multiplexed immunofluorescence (MxIF) was used to generate single cell data for 43 protein markers representing all cancer hallmarks, Genomic sequencing (exome and RNA (normal and tumor) and magnetic resonance imaging (MRI) quantitative features (protocols were T1-post, FLAIR and ADC) from whole tumor, peritumoral edema and enhancing core vs equivalent normal region were also collected from patients. Based on MxIF analysis, 85,767 cells (glioma cases) and 56,304 cells (GBM cases) were used to generate cell-level data for 24 biomarkers. K-means clustering was used to generate 7 distinct groups of cells with divergent biomarker profiles and deconvolution was used to assign RNA data into three classes. Spatial and molecular heterogeneity metrics were generated for the cell data. All features were compared between IDH mt and IDHwt patients and were finally combined to provide a holistic/integrated comparison. Protein expression by hallmark was generally lower in the IDHmt vs wt patients. Molecular and spatial heterogeneity scores for angiogenesis and cell invasion also differed between IDHmt and wt gliomas irrespective of prior treatment and tumor grade; these differences also persisted in the MR imaging features of peritumoral edema and contrast enhancement volumes. A coherent picture of enhanced angiogenesis in IDHwt tumors was derived from multiple platforms (genomic, proteomic and imaging) and scales from individual proteins to cell clusters and heterogeneity, as well as bulk tumor RNA and imaging features. Longer overall survival for IDH1mt glioma patients may reflect mutation-driven alterations in cellular, molecular, and spatial heterogeneity which manifest in discernable radiological manifestations.https://doi.org/10.1371/journal.pone.0219724 |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Michael E Berens Anup Sood Jill S Barnholtz-Sloan John F Graf Sanghee Cho Seungchan Kim Jeffrey Kiefer Sara A Byron Rebecca F Halperin Sara Nasser Jonathan Adkins Lori Cuyugan Karen Devine Quinn Ostrom Marta Couce Leo Wolansky Elizabeth McDonough Shannon Schyberg Sean Dinn Andrew E Sloan Michael Prados Joanna J Phillips Sarah J Nelson Winnie S Liang Yousef Al-Kofahi Mirabela Rusu Maria I Zavodszky Fiona Ginty |
spellingShingle |
Michael E Berens Anup Sood Jill S Barnholtz-Sloan John F Graf Sanghee Cho Seungchan Kim Jeffrey Kiefer Sara A Byron Rebecca F Halperin Sara Nasser Jonathan Adkins Lori Cuyugan Karen Devine Quinn Ostrom Marta Couce Leo Wolansky Elizabeth McDonough Shannon Schyberg Sean Dinn Andrew E Sloan Michael Prados Joanna J Phillips Sarah J Nelson Winnie S Liang Yousef Al-Kofahi Mirabela Rusu Maria I Zavodszky Fiona Ginty Multiscale, multimodal analysis of tumor heterogeneity in IDH1 mutant vs wild-type diffuse gliomas. PLoS ONE |
author_facet |
Michael E Berens Anup Sood Jill S Barnholtz-Sloan John F Graf Sanghee Cho Seungchan Kim Jeffrey Kiefer Sara A Byron Rebecca F Halperin Sara Nasser Jonathan Adkins Lori Cuyugan Karen Devine Quinn Ostrom Marta Couce Leo Wolansky Elizabeth McDonough Shannon Schyberg Sean Dinn Andrew E Sloan Michael Prados Joanna J Phillips Sarah J Nelson Winnie S Liang Yousef Al-Kofahi Mirabela Rusu Maria I Zavodszky Fiona Ginty |
author_sort |
Michael E Berens |
title |
Multiscale, multimodal analysis of tumor heterogeneity in IDH1 mutant vs wild-type diffuse gliomas. |
title_short |
Multiscale, multimodal analysis of tumor heterogeneity in IDH1 mutant vs wild-type diffuse gliomas. |
title_full |
Multiscale, multimodal analysis of tumor heterogeneity in IDH1 mutant vs wild-type diffuse gliomas. |
title_fullStr |
Multiscale, multimodal analysis of tumor heterogeneity in IDH1 mutant vs wild-type diffuse gliomas. |
title_full_unstemmed |
Multiscale, multimodal analysis of tumor heterogeneity in IDH1 mutant vs wild-type diffuse gliomas. |
title_sort |
multiscale, multimodal analysis of tumor heterogeneity in idh1 mutant vs wild-type diffuse gliomas. |
publisher |
Public Library of Science (PLoS) |
series |
PLoS ONE |
issn |
1932-6203 |
publishDate |
2019-01-01 |
description |
Glioma is recognized to be a highly heterogeneous CNS malignancy, whose diverse cellular composition and cellular interactions have not been well characterized. To gain new clinical- and biological-insights into the genetically-bifurcated IDH1 mutant (mt) vs wildtype (wt) forms of glioma, we integrated data from protein, genomic and MR imaging from 20 treatment-naïve glioma cases and 16 recurrent GBM cases. Multiplexed immunofluorescence (MxIF) was used to generate single cell data for 43 protein markers representing all cancer hallmarks, Genomic sequencing (exome and RNA (normal and tumor) and magnetic resonance imaging (MRI) quantitative features (protocols were T1-post, FLAIR and ADC) from whole tumor, peritumoral edema and enhancing core vs equivalent normal region were also collected from patients. Based on MxIF analysis, 85,767 cells (glioma cases) and 56,304 cells (GBM cases) were used to generate cell-level data for 24 biomarkers. K-means clustering was used to generate 7 distinct groups of cells with divergent biomarker profiles and deconvolution was used to assign RNA data into three classes. Spatial and molecular heterogeneity metrics were generated for the cell data. All features were compared between IDH mt and IDHwt patients and were finally combined to provide a holistic/integrated comparison. Protein expression by hallmark was generally lower in the IDHmt vs wt patients. Molecular and spatial heterogeneity scores for angiogenesis and cell invasion also differed between IDHmt and wt gliomas irrespective of prior treatment and tumor grade; these differences also persisted in the MR imaging features of peritumoral edema and contrast enhancement volumes. A coherent picture of enhanced angiogenesis in IDHwt tumors was derived from multiple platforms (genomic, proteomic and imaging) and scales from individual proteins to cell clusters and heterogeneity, as well as bulk tumor RNA and imaging features. Longer overall survival for IDH1mt glioma patients may reflect mutation-driven alterations in cellular, molecular, and spatial heterogeneity which manifest in discernable radiological manifestations. |
url |
https://doi.org/10.1371/journal.pone.0219724 |
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