High-Grade Gliomas

Paediatric Molecular Pathology Team

Section: Section of Paediatric Oncology

Tumours of the central nervous system account for 20-25% of paediatric cancer, affecting about 1 in 2500 children, and are the leading cause of cancer-related death. Approximately 40% of all paediatric brain tumours are astrocytomas (gliomas), and they are divided according to the World Health Organisation (WHO) classification into low-grade (grade I and II) and high-grade (grade III and IV) tumours. Although advances in treatment have led to improved survival for some children with brain tumours, those with high-grade gliomas invariably have a poor outcome, with 5-year survival rates of less than 20% for children with anaplastic astrocytoma and glioblastoma multiforme, and median survival of only 9-12 months for children with intrinsic brainstem glioma.

Work is beginning in our laboratory designed to address the paucity of data in high grade gliomas, and to improve our understanding of the molecular pathogenesis of the disease. We aim to identify and validate novel molecular markers for use in tumour classification, treatment response and therapeutics.

Molecular genetic analysis of paediatric high-grade glioma

We are carrying out a detailed molecular profiling analysis on a series of paediatric high-grade glioma samples, with the specific aims of correlating genomic imbalances and gene expression changes with clinical outcome, histological grade, disease location and age at diagnosis. We will begin by screening both cell lines and primary tumours from children and adults for the presence of targets for existing novel or innovative therapies. This will initially focus on a cohort of formalin-fixed, paraffin-embedded samples, and utilise our experience with chromogenic in situ hybridisation (CISH) and immunohistochemistry to demonstrate a proof of principle in a screen for the presence of receptor tyrosine kinases.

Characterisation of paediatric high-grade glioma cell lines

One important factor hampering preclinical work in paediatric patients is the relative lack of cell lines derived from high-grade glioma patients of this age group. It is currently unclear whether the well-established adult lines commonly used are representative of the underlying molecular genetics of childhood tumours. We aim to determine the patterns of DNA copy number aberrations and gene expression in the high-grade glioma cell lines, and to determine the differences and similarities between paediatric and adult-derived cells, as well as between cell line and primary tumours, in order to identify the most appropriate model systems for functional and preclinical work.