Genetic pathogenesis of paediatric astrocytoma and ependymoma

Brain tumours are the leading cause of cancer-related deaths in children <15 years of age. Approximately 400 new cases of primary CNS tumours are diagnosed in the paediatric population per annum in the UK and the majority of these are astrocytoma.

Approximately one-fifth will be malignant astrocytoma (WHO grade III or IV) and less than 20% of these patients survive 2 years from diagnosis. Ependymomas account for approximately 10% of all intracranial tumours in childhood and a higher proportion, up to 30%, in children <3 years. Intracranial ependymomas have a propensity to recur and 5-year survival rates are only 50%.

Through extensive genomic analyses of childhood astrocytoma and ependymoma, we have demonstrated that these paediatric tumours do have harbour the gene deletions, amplifications and mutations which are characteristic in their adult counterparts. Using global gene expression analysis of > 70 paediatric ependymoma and astrocytoma samples, we have identified biological pathways associated with cell proliferation, cell adhesion, invasion and migration, angiogenesis and apoptosis which are disrupted in these tumours. In paediatric astrocytoma, we are evaluating the therapeutic potential by switching off their expression with messenger RNA interference technology and assessing the consequences on tumour cell behaviour such proliferation, migration and invasion and programmed cell death (apoptosis).

Gene silencing through DNA methylation is one of the most widespread and powerful mechanisms by which genes are turned off in many tumour types. We have demonstrated that DNA methylation is an important mechanism in the down-regulation of a novel putative tumour suppressor gene, Chibby, in ependymoma.

Chibby acts as a tumour suppressor by inhibiting Wnt/β-catenin mediated transcriptional activation. We have identified a further 115 genes which are switched off through methylation in ependymoma short-term cell cultures and we are investigating the ability of methylated genes to function as suppressors of tumour growth after their reintroduction into ependymoma cultures. 

Evaluating their effects on the Wnt and apoptotic signalling pathways and other mechanisms of growth regulation in ependymoma may provide new therapeutic approaches for treatment.

It is highly probable that aberrant methylation is also an important mechanism of gene silencing in paediatric astrocytoma.

Having proven the efficacy of pharmacological unmasking and global expression analysis in identifying methylated genes in ependymoma, we propose to duplicusingate this experimental strategy in paediatric astrocytoma of all grades of malignancy in order to understand their biological and clinical behaviour and to design new drugs to treat these tumours.