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

Stéphanie Puget ,Vladimir Lazar,Dorine A Bax,Catherine Richon,Pascale Varlet,Philippe Dessen,Felipe Andreiuolo,Chris Jones,Bastien Job,Thomas Roujeau,Cathy Philippe,Jacques Grill,Dina Carvalho,Gilles Vassal,Birgit Geoerger,Christian Sainte‐Rose ,Ricardo Coelho Reis ,Léa Guerrini-Rousseau ,Marie‐Pierre Junier ,Gwénaël Le Teuff

doi:10.1371/journal.pone.0030313

Abstract

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.

Highlights

Brain tumors are the leading cause of cancer-related morbidity and mortality in children and adolescents, malignant gliomas carrying the worst prognosis among them [1]
We report the first comprehensive genomic analysis of Diffuse intrinsic pontine glioma (DIPG) samples taken at diagnosis, and identify key biological features which distinguish them from other pediatric supratentorial HGG
The gene expression signatures associated with the location of a tumour was associated with differential reprogramming of embryonic signaling organizers, reflecting the discrete developmental origins of HGG presenting in different locations in the brain

Summary

Introduction

Brain tumors are the leading cause of cancer-related morbidity and mortality in children and adolescents, malignant gliomas carrying the worst prognosis among them [1]. Malignant gliomas that diffusely infiltrate the brainstem appear almost exclusively during childhood and adolescence and have a relatively homogenous presentation and dismal prognosis. The vast majority of children succumb to their disease within 2 years of diagnosis. These tumors are unresectable and radiotherapy is the only treatment offering a significant but transient improvement. Trials have been implemented so far based on the assumption that biologic properties of these brainstem gliomas of children are identical to cerebral high-grade gliomas of adults [4,5]. Recent data suggest that pediatric high-grade gliomas differ from their adult counterparts [6,7,8,9], and that there may be biological distinctions between childhood gliomas presenting in the brainstem compared with supratentorial ones [10]

Methods

Results

Conclusion