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

By S. Puget, C. Philippe, D. Bax, B. Job, P. Varlet, M. Junier, F. Andreiuolo, Dina Carvalho, Ricardo Reis, L. Guerrini-Rousseau and 10 more. 2012

243 citations recorded by the source corpus.

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.

Subfields: Genetics, Neurology, Pulmonary and Respiratory Medicine

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Citations in the corpus

Glioblastoma: pathology, molecular mechanisms and markers (2015, background): “Another alteration found in pediatric GBMs is a higher amplification frequency of the PDGFRA gene that is associated with activation of a PDGFRA-driven gene expression signature [125, 126, 130].”
Hotspot mutations in H3F3A and IDH1 define distinct epigenetic and biological subgroups of glioblastoma. (2012, background): “While recurrent focal amplification of PDGFRA has been suggested as a key oncogenic event in pediatric DIPGs in some studies (Paugh et al., 2011; Puget et al., 2012; Zarghooni et al., 2010), midline-associated tumors in the K27 or OLIG2/FOXG1 subgroups (including ten brainstem gliomas with known PDG”
Integrated Molecular Meta-Analysis of 1,000 Pediatric High-Grade and Diffuse Intrinsic Pontine Glioma (2017, background): “…include known oncogenes in adult glioma and other tumors with an elevated frequency in the childhood setting (e.g., PDGFRA) (Paugh et al., 2013; Puget et al., 2012) or certain rare histological variants (e.g., BRAF V600E) (Nicolaides et al., 2011; Schiffman et al., 2010), as well as others…”