Ward, Samantha Jane; (2003) Genetic abnormalities in paediatric glial tumours. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Primary central nervous system tumours account for 9-20% of all malignancies in the paediatric age group with astrocytoma being the most common tumour type and ependymoma the third. Little in known about the genetic aberrations that occur in paediatric glial tumours, and there are no definitive genetic markers that can determine outcome in children with these tumours. The aims of the present study were to identify consistent regions of genetic loss and gain in paediatric ependymoma and astrocytoma using comparative genomic hybridisation (CGH) and to determine whether any chromosome abnormalities can be used as prognostic markers. CGH was used to analyse 51 ependymoma and 64 astrocytoma from 110 patients for regions of genomic imbalance. A large proportion of the samples (65.5%) had normal karyotypes. In both ependymoma and astrocytoma, gain of 4q was the most frequent region of gain and loss of chromosome 19 was the most frequently deleted region. With a few exceptions loss of 1p was seen independently of gain of 1q in ependymoma, allowing the ependymoma to be classified into three groups based on CNAs. The study showed the alterations found in paediatric astrocytoma to differ from those seen in adult tumours, suggesting a different pathway leads to their formation. MDR1 expression was observed in 65% of ependymoma suggesting this gene may have a role in the drug resistant phenotype of some ependymoma. A number of potential prognostic markers were identified, including increased survival in ependymoma patients with monosomy 19. Gain of 7q and loss of 12q were associated with recurrent ependymoma. Loss of 16q was seen more frequently in primary tumours that had recurred than those with no tumour recurrence. The presence of a normal karyotype was associated with increased survival in patients with low-grade astrocytoma. Decreased survival was seen in astrocytoma patients with either gain of 2q, 5q and 7 or loss of 16p.

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