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HGG-26. SINGLE-CELL RNA-SEQ OF PEDIATRIC HIGH-GRADE GLIOMAS IDENTIFIES COMMON ONCOGENIC PROCESSES AMONG DISTINCT TUMOR HISTOLOGIES

BACKGROUND: Pediatric high-grade glioma (PHGG) is a deadly childhood brain tumor that responds poorly to treatment. PHGG comprises two major subtypes: cortical tumors with wild-type H3K27 and diffuse midline gliomas (DMG) that occur in the midline and have characteristic H3K27M mutations. Cortical P...

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Autores principales: DeSisto, John, Donson, Andrew, Fu, Rui, Sanford, Bridget, Riemondy, Kent, Green, Adam
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Oxford University Press 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8168164/
http://dx.doi.org/10.1093/neuonc/noab090.090
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author DeSisto, John
Donson, Andrew
Fu, Rui
Sanford, Bridget
Riemondy, Kent
Green, Adam
author_facet DeSisto, John
Donson, Andrew
Fu, Rui
Sanford, Bridget
Riemondy, Kent
Green, Adam
author_sort DeSisto, John
collection PubMed
description BACKGROUND: Pediatric high-grade glioma (PHGG) is a deadly childhood brain tumor that responds poorly to treatment. PHGG comprises two major subtypes: cortical tumors with wild-type H3K27 and diffuse midline gliomas (DMG) that occur in the midline and have characteristic H3K27M mutations. Cortical PHGG is heterogeneous with multiple molecular subtypes. In order to identify underlying commonalities in cortical PHGG that might lead to better treatment modalities, we performed molecular profiling, including single-cell RNA-Seq (scRNA-Seq), on PHGG samples from Children’s Hospital Colorado. METHODS: Nineteen cortical PHGG tumor samples, one DMG and one normal margin sample obtained at biopsy were disaggregated to isolate viable cells. Fifteen were glioblastomas (GBM), including five with epithelioid and/or giant cell features and five radiation-induced glioblastomas (RIG). There were also four non-GBM PHGG. We performed scRNA-Seq using 10X Genomics v.3 library preparation to enable capture of infiltrating immune cells. We also performed bulk RNA-Seq and DNA methylation profiling. RESULTS: After eliminating patient-specific and cell-cycle effects, RIG, epithelioid GBM, and other GBM each formed identifiable subgroups in bulk RNA-Seq and scRNA-Seq datasets. In the scRNA-Seq data, clusters with cells from multiple tumor samples included a PDGFRA-positive population expressing oligodendrocyte progenitor markers, astrocytic, mesenchymal and stemlike populations, macrophage/monocyte immune cells, and a smaller T-cell population. Analyses of DNA methylation data showed PDGFRA and CDK4 amplification and CDKN2A deletion are common alterations among PHGG. Inferred copy number variation analysis of the single-cell data confirmed that individual tumors include populations that both include and lack the molecular alterations identified in the methylation data. RNA velocity studies to define tumor cells of origin and further analyses of the immune cell populations are underway. CONCLUSIONS: Single-cell analysis of PHGG confirms a large degree of tumor heterogeneity but also shows that PHGG have stemlike, mesenchymal and immune cell populations with common characteristics.
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spelling pubmed-81681642021-06-02 HGG-26. SINGLE-CELL RNA-SEQ OF PEDIATRIC HIGH-GRADE GLIOMAS IDENTIFIES COMMON ONCOGENIC PROCESSES AMONG DISTINCT TUMOR HISTOLOGIES DeSisto, John Donson, Andrew Fu, Rui Sanford, Bridget Riemondy, Kent Green, Adam Neuro Oncol High Grade Gliomas BACKGROUND: Pediatric high-grade glioma (PHGG) is a deadly childhood brain tumor that responds poorly to treatment. PHGG comprises two major subtypes: cortical tumors with wild-type H3K27 and diffuse midline gliomas (DMG) that occur in the midline and have characteristic H3K27M mutations. Cortical PHGG is heterogeneous with multiple molecular subtypes. In order to identify underlying commonalities in cortical PHGG that might lead to better treatment modalities, we performed molecular profiling, including single-cell RNA-Seq (scRNA-Seq), on PHGG samples from Children’s Hospital Colorado. METHODS: Nineteen cortical PHGG tumor samples, one DMG and one normal margin sample obtained at biopsy were disaggregated to isolate viable cells. Fifteen were glioblastomas (GBM), including five with epithelioid and/or giant cell features and five radiation-induced glioblastomas (RIG). There were also four non-GBM PHGG. We performed scRNA-Seq using 10X Genomics v.3 library preparation to enable capture of infiltrating immune cells. We also performed bulk RNA-Seq and DNA methylation profiling. RESULTS: After eliminating patient-specific and cell-cycle effects, RIG, epithelioid GBM, and other GBM each formed identifiable subgroups in bulk RNA-Seq and scRNA-Seq datasets. In the scRNA-Seq data, clusters with cells from multiple tumor samples included a PDGFRA-positive population expressing oligodendrocyte progenitor markers, astrocytic, mesenchymal and stemlike populations, macrophage/monocyte immune cells, and a smaller T-cell population. Analyses of DNA methylation data showed PDGFRA and CDK4 amplification and CDKN2A deletion are common alterations among PHGG. Inferred copy number variation analysis of the single-cell data confirmed that individual tumors include populations that both include and lack the molecular alterations identified in the methylation data. RNA velocity studies to define tumor cells of origin and further analyses of the immune cell populations are underway. CONCLUSIONS: Single-cell analysis of PHGG confirms a large degree of tumor heterogeneity but also shows that PHGG have stemlike, mesenchymal and immune cell populations with common characteristics. Oxford University Press 2021-06-01 /pmc/articles/PMC8168164/ http://dx.doi.org/10.1093/neuonc/noab090.090 Text en © The Author(s) 2021. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com. https://creativecommons.org/licenses/by-nc/4.0/This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/ (https://creativecommons.org/licenses/by-nc/4.0/) ), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com
spellingShingle High Grade Gliomas
DeSisto, John
Donson, Andrew
Fu, Rui
Sanford, Bridget
Riemondy, Kent
Green, Adam
HGG-26. SINGLE-CELL RNA-SEQ OF PEDIATRIC HIGH-GRADE GLIOMAS IDENTIFIES COMMON ONCOGENIC PROCESSES AMONG DISTINCT TUMOR HISTOLOGIES
title HGG-26. SINGLE-CELL RNA-SEQ OF PEDIATRIC HIGH-GRADE GLIOMAS IDENTIFIES COMMON ONCOGENIC PROCESSES AMONG DISTINCT TUMOR HISTOLOGIES
title_full HGG-26. SINGLE-CELL RNA-SEQ OF PEDIATRIC HIGH-GRADE GLIOMAS IDENTIFIES COMMON ONCOGENIC PROCESSES AMONG DISTINCT TUMOR HISTOLOGIES
title_fullStr HGG-26. SINGLE-CELL RNA-SEQ OF PEDIATRIC HIGH-GRADE GLIOMAS IDENTIFIES COMMON ONCOGENIC PROCESSES AMONG DISTINCT TUMOR HISTOLOGIES
title_full_unstemmed HGG-26. SINGLE-CELL RNA-SEQ OF PEDIATRIC HIGH-GRADE GLIOMAS IDENTIFIES COMMON ONCOGENIC PROCESSES AMONG DISTINCT TUMOR HISTOLOGIES
title_short HGG-26. SINGLE-CELL RNA-SEQ OF PEDIATRIC HIGH-GRADE GLIOMAS IDENTIFIES COMMON ONCOGENIC PROCESSES AMONG DISTINCT TUMOR HISTOLOGIES
title_sort hgg-26. single-cell rna-seq of pediatric high-grade gliomas identifies common oncogenic processes among distinct tumor histologies
topic High Grade Gliomas
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8168164/
http://dx.doi.org/10.1093/neuonc/noab090.090
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