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Mesenchymal Transition and PDGFRA Amplification/Mutation Are Key Distinct Oncogenic Events in Pediatric Diffuse Intrinsic Pontine Gliomas

Diffuse intrinsic pontine glioma (DIPG) is one of the most frequent malignant pediatric brain tumor and its prognosis is universaly fatal. No significant improvement has been made in last thirty years over the standard treatment with radiotherapy. To address the paucity of understanding of DIPGs, we...

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Autores principales: Puget, Stephanie, Philippe, Cathy, Bax, Dorine A., Job, Bastien, Varlet, Pascale, Junier, Marie-Pierre, Andreiuolo, Felipe, Carvalho, Dina, Reis, Ricardo, Guerrini-Rousseau, Lea, Roujeau, Thomas, Dessen, Philippe, Richon, Catherine, Lazar, Vladimir, Le Teuff, Gwenael, Sainte-Rose, Christian, Geoerger, Birgit, Vassal, Gilles, Jones, Chris, Grill, Jacques
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2012
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3289615/
https://www.ncbi.nlm.nih.gov/pubmed/22389665
http://dx.doi.org/10.1371/journal.pone.0030313
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author Puget, Stephanie
Philippe, Cathy
Bax, Dorine A.
Job, Bastien
Varlet, Pascale
Junier, Marie-Pierre
Andreiuolo, Felipe
Carvalho, Dina
Reis, Ricardo
Guerrini-Rousseau, Lea
Roujeau, Thomas
Dessen, Philippe
Richon, Catherine
Lazar, Vladimir
Le Teuff, Gwenael
Sainte-Rose, Christian
Geoerger, Birgit
Vassal, Gilles
Jones, Chris
Grill, Jacques
author_facet Puget, Stephanie
Philippe, Cathy
Bax, Dorine A.
Job, Bastien
Varlet, Pascale
Junier, Marie-Pierre
Andreiuolo, Felipe
Carvalho, Dina
Reis, Ricardo
Guerrini-Rousseau, Lea
Roujeau, Thomas
Dessen, Philippe
Richon, Catherine
Lazar, Vladimir
Le Teuff, Gwenael
Sainte-Rose, Christian
Geoerger, Birgit
Vassal, Gilles
Jones, Chris
Grill, Jacques
author_sort Puget, Stephanie
collection PubMed
description Diffuse intrinsic pontine glioma (DIPG) is one of the most frequent malignant pediatric brain tumor and its prognosis is universaly fatal. No significant improvement has been made in last thirty years over the standard treatment with radiotherapy. To address the paucity of understanding of DIPGs, we have carried out integrated molecular profiling of a large series of samples obtained with stereotactic biopsy at diagnosis. While chromosomal imbalances did not distinguish DIPG and supratentorial tumors on CGHarrays, gene expression profiling revealed clear differences between them, with brainstem gliomas resembling midline/thalamic tumours, indicating a closely-related origin. Two distinct subgroups of DIPG were identified. The first subgroup displayed mesenchymal and pro-angiogenic characteristics, with stem cell markers enrichment consistent with the possibility to grow tumor stem cells from these biopsies. The other subgroup displayed oligodendroglial features, and appeared largely driven by PDGFRA, in particular through amplification and/or novel missense mutations in the extracellular domain. Patients in this later group had a significantly worse outcome with an hazard ratio for early deaths, ie before 10 months, 8 fold greater that the ones in the other subgroup (p = 0.041, Cox regression model). The worse outcome of patients with the oligodendroglial type of tumors was confirmed on a series of 55 paraffin-embedded biopsy samples at diagnosis (median OS of 7.73 versus 12.37 months, p = 0.045, log-rank test). Two distinct transcriptional subclasses of DIPG with specific genomic alterations can be defined at diagnosis by oligodendroglial differentiation or mesenchymal transition, respectively. Classifying these tumors by signal transduction pathway activation and by mutation in pathway member genes may be particularily valuable for the development of targeted therapies.
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spelling pubmed-32896152012-03-02 Mesenchymal Transition and PDGFRA Amplification/Mutation Are Key Distinct Oncogenic Events in Pediatric Diffuse Intrinsic Pontine Gliomas Puget, Stephanie Philippe, Cathy Bax, Dorine A. Job, Bastien Varlet, Pascale Junier, Marie-Pierre Andreiuolo, Felipe Carvalho, Dina Reis, Ricardo Guerrini-Rousseau, Lea Roujeau, Thomas Dessen, Philippe Richon, Catherine Lazar, Vladimir Le Teuff, Gwenael Sainte-Rose, Christian Geoerger, Birgit Vassal, Gilles Jones, Chris Grill, Jacques PLoS One Research Article Diffuse intrinsic pontine glioma (DIPG) is one of the most frequent malignant pediatric brain tumor and its prognosis is universaly fatal. No significant improvement has been made in last thirty years over the standard treatment with radiotherapy. To address the paucity of understanding of DIPGs, we have carried out integrated molecular profiling of a large series of samples obtained with stereotactic biopsy at diagnosis. While chromosomal imbalances did not distinguish DIPG and supratentorial tumors on CGHarrays, gene expression profiling revealed clear differences between them, with brainstem gliomas resembling midline/thalamic tumours, indicating a closely-related origin. Two distinct subgroups of DIPG were identified. The first subgroup displayed mesenchymal and pro-angiogenic characteristics, with stem cell markers enrichment consistent with the possibility to grow tumor stem cells from these biopsies. The other subgroup displayed oligodendroglial features, and appeared largely driven by PDGFRA, in particular through amplification and/or novel missense mutations in the extracellular domain. Patients in this later group had a significantly worse outcome with an hazard ratio for early deaths, ie before 10 months, 8 fold greater that the ones in the other subgroup (p = 0.041, Cox regression model). The worse outcome of patients with the oligodendroglial type of tumors was confirmed on a series of 55 paraffin-embedded biopsy samples at diagnosis (median OS of 7.73 versus 12.37 months, p = 0.045, log-rank test). Two distinct transcriptional subclasses of DIPG with specific genomic alterations can be defined at diagnosis by oligodendroglial differentiation or mesenchymal transition, respectively. Classifying these tumors by signal transduction pathway activation and by mutation in pathway member genes may be particularily valuable for the development of targeted therapies. Public Library of Science 2012-02-28 /pmc/articles/PMC3289615/ /pubmed/22389665 http://dx.doi.org/10.1371/journal.pone.0030313 Text en Puget et al. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Puget, Stephanie
Philippe, Cathy
Bax, Dorine A.
Job, Bastien
Varlet, Pascale
Junier, Marie-Pierre
Andreiuolo, Felipe
Carvalho, Dina
Reis, Ricardo
Guerrini-Rousseau, Lea
Roujeau, Thomas
Dessen, Philippe
Richon, Catherine
Lazar, Vladimir
Le Teuff, Gwenael
Sainte-Rose, Christian
Geoerger, Birgit
Vassal, Gilles
Jones, Chris
Grill, Jacques
Mesenchymal Transition and PDGFRA Amplification/Mutation Are Key Distinct Oncogenic Events in Pediatric Diffuse Intrinsic Pontine Gliomas
title Mesenchymal Transition and PDGFRA Amplification/Mutation Are Key Distinct Oncogenic Events in Pediatric Diffuse Intrinsic Pontine Gliomas
title_full Mesenchymal Transition and PDGFRA Amplification/Mutation Are Key Distinct Oncogenic Events in Pediatric Diffuse Intrinsic Pontine Gliomas
title_fullStr Mesenchymal Transition and PDGFRA Amplification/Mutation Are Key Distinct Oncogenic Events in Pediatric Diffuse Intrinsic Pontine Gliomas
title_full_unstemmed Mesenchymal Transition and PDGFRA Amplification/Mutation Are Key Distinct Oncogenic Events in Pediatric Diffuse Intrinsic Pontine Gliomas
title_short Mesenchymal Transition and PDGFRA Amplification/Mutation Are Key Distinct Oncogenic Events in Pediatric Diffuse Intrinsic Pontine Gliomas
title_sort mesenchymal transition and pdgfra amplification/mutation are key distinct oncogenic events in pediatric diffuse intrinsic pontine gliomas
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3289615/
https://www.ncbi.nlm.nih.gov/pubmed/22389665
http://dx.doi.org/10.1371/journal.pone.0030313
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