Please use this identifier to cite or link to this item: http://hdl.handle.net/1822/63284

TitleMesenchymal transition and PDGFRA amplification/mutation are key distinct oncogenic events in pediatric diffuse intrinsic pontine gliomas
Author(s)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
KeywordsBrain Stem Neoplasms
Epithelial-Mesenchymal Transition
Gene Expression Profiling
Humans
Immunohistochemistry
In Vitro Techniques
Mutation
Receptor, Platelet-Derived Growth Factor alpha
Signal Transduction
Snail Family Transcription Factors
Transcription Factors
Issue date2012
PublisherPublic Library of Science (PLOS)
JournalPLoS ONE
CitationPuget S, Philippe C, Bax DA, Job B, Varlet P, Junier M-P, et al. (2012) Mesenchymal Transition and PDGFRA Amplification/Mutation Are Key Distinct Oncogenic Events in Pediatric Diffuse Intrinsic Pontine Gliomas. PLoS ONE 7(2): e30313. https://doi.org/10.1371/journal.pone.0030313
Abstract(s)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.
TypeArticle
URIhttp://hdl.handle.net/1822/63284
DOI10.1371/journal.pone.0030313
ISSN1932-6203
Publisher versionhttps://journals.plos.org/plosone/article?id=10.1371/journal.pone.0030313
Peer-Reviewedyes
AccessOpen access
Appears in Collections:ICVS - Artigos em Revistas Internacionais com Referee

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