Research Interest
Molecular pathology of paediatric high grade glioma
High grade glioma in children is a heterogeneous collection of tumours with a generally poor clinical outcome that, like similar lesions in adults, has changed little in the past four decades. Although they have traditionally been classified in the same way as those occurring in older patients, childhood tumours show differences in the frequency of malignant transformation, as well as the site of presentation, with diffuse intrinsic pontine gliomas rarely seen in adults. Until recently, it was unclear whether these clinical distinctions were reflected at the genetic level.
Our lab has contributed to this increased understanding of the paediatric high grade glioma genome by carrying out the largest studies yet published in supratentorial tumours (collaboration with Suzanne Baker, St Jude Children’s Research Hospital and Richard Grundy, University of Nottingham) and diffuse intrinsic pontine glioma (collaboration with Jacques Grill, Institut Gustav Roussy and Stephanie Puget, Necker Hospital for Sick Children), with these findings validated in our own series of archival pathology specimens.
The key message from these studies is the distinct biological difference between these tumours based upon the age at which they occur, and the site of presentation. The most common alteration in the childhood setting is PDGFRA amplification and/or mutation, which is found more frequently than in adult tumours, and without the presence of IDH1 mutations found in adult, secondary glioblastoma. PDGFRA signalling appears to be both preferentially, and differentially activated in paediatric high grade glioma, and we have identified a specific gene expression signature to be present in a subset of tumours independent of gene copy number. PDGFRA, as well as other potential novel drug targets, are being actively studied for their potential clinical applications using paediatric glioma-specific preclinical model systems.
We are continuing to explore the genomics of these tumours through ongoing collaborative collections, and the application of next-generation sequencing techniques. We are also co-ordinating (with Andre von Beuren, Hamburg, and Michael Baudis, Zurich) an international systematic review and meta-analysis of all published genomic data on paediatric high grade glioma in order to maximise the information we can derive from these rare tumours.
Selected recent publications
1. Puget S, Philippe C, Bax DA, Job B, Varlet P, Junier MP, Andreiuolo P, Juber C, Opolon P, Carvalho D, Reis RM, Guerrini-Rousseau L, Roujeau T, Dessen P, Richon C, Lazar V, Sainte-Rose C, Vassal G, Jones C*, Geoerger B*, Grill J* (submitted) “Mesenchymal transition and PDGFRA pathway activation through amplification and/or mutation are key distinct oncogenic events in diffuse intrinsic pontine gliomas”
2. Bax DA*, Mackay A*, Little SE, Carvalho D, Viana -Pereira M, Tamber N, Grigoriadis A, Ashworth A, Reis RM, Ellison DW, Al-Sarraj S, Hargrave D and Jones C (2010) “A distinct spectrum of copy number aberrations in paediatric high grade gliomas” Clin Cancer Res 16:3368-3377
3. Paugh BS*, Qu C*, Jones C*, Liu Z, Adamowicz-Brice M, Zhang J, Bax DA, Coyle B, Barrow J, Hargrave D, Lowe J, Gajjar A, Zhao W, Broniscer A, Ellison DW, Grundy R and Baker SJ (2010) “Integrated molecular genetic profiling of paediatric high grade gliomas reveals key differences with the adult disease” J Clin Oncol 28:3061-3068
Experimental Therapeutics
Our laboratory is carrying out preclinical evaluation of novel compounds targeting genes and signalling pathways identified to be important in the disease.
Genomic profiling of paediatric high grade glioma
To make the greatest progress in these rare tumours, it would be beneficial to pool as much data as possible, in order to better define the molecular alterations driving this disease.
