Genetic aberrations in high-grade astrocytic gliomas
Astrocytic gliomas are the most common tumours arising in the central nervous system. This thesis focuses on examining genetic changes in high-grade astrocytic gliomas. It describes the development of an analytical tool to facilitate systematic analysis of array comparative genomic hybridisation (CGH) results and catalogues copy number changes in high-grade astrocytic glioma cell lines and patient samples. Molecular cytogenetic analysis of chromosome 6 was used to explore the relationship between copy number changes and positional aberrations. Three regions of copy number associated with translocation breakpoints are described. The first translocation associated with a copy number change was in the cell line U87, loss of 6pter to 6p21 arises from an unbalanced translocation between chromosomes 6 and 7, with the breakpoint at 6p21 being close to the POLH and GTPBP2 genes. The second is a discrete deletion in 6q23- 24 in U87 is associated with a translocation between chromosomes 6 and 12, and involves several genes including MAP3K5 and MAP7. The third is a discrete deletion of 6q26-27 in cell lines CRL2020 and CRL1620 involving IGF2R, PARK2, PACRG and QKI is associated chromosome translocations. Inactivation of a tumour suppressor gene near the breakpoint may be a primary consequence of certain translocations in solid tumours, in contrast to the oncogenic gene fusions present in haematological and mesenchymal malignancies.