Enyakoit, G.O.; (2008) Cytogenetic analysis of DNA copy number aberrations in high malignancy grade astrocytomas. Doctoral thesis , University of London.

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Abstract

Astrocytomas are the most common variety of primary tumours of the central nervous system (CNS). The incidence increases with age, peaking in patients aged 65--75 years. They are generally unresponsive to treatment, and most patients die within one year of diagnosis. Recent genetic studies of astrocytoma susceptibility syndromes, familial- and sporadic astrocytomas have led to the discovery of many genes and molecular mechanisms underlying astrocytoma oncogenesis. A few of the genes involved in inherited astrocytoma associated-syndromes (e.g., Cowden and Li-Fraumeni syndromes) are also strongly implicated in sporadic astrocytomas. However for several other well characterised genes i.e. those mutated in Tuberous sclerosis (TSC) and Neurofibromatosis (NF) any evidence for involvement in sporadic astrocytomas is much less clear. The objective of this study was to undertake a genome-wide survey of high malignancy grade astrocytomas with a view to ascertaining the distribution and prevalence of copy number aberrations, search for associations with prognosis and outcomes to treatment, and to discover possible novel pathways of oncogenesis. Thirty-two high malignancy grade astrocytomas were investigated. Twenty were available as frozen biopsies and 12 as short-term cell cultures. Genomic profiling of all 32, comprising 6 tumours of WHO Grade III and 26 of Grade IV, was achieved by the method of Comparative Genomic Hybridisation onto metaphase chromosomes. 7 of the tumours were investigated by array CGH, with one further investigated by MFISH. Two tumours did not reveal aberrations. For the other 30 tumours, data pooled from a minimum of 10 profiles of each tumour were analysed. Recurrent DNA copy number gains and losses were detected across the genome. In a number of tumours aberrations spanned loci of established candidate genes previously associated with sporadic astrocytomas, on chromosomes 7, 9p, lOq, 12q, 13q and 17p. In addition over 70% of 'sporadic' tumours appeared to have DNA-copy number aberrations implicating genes with established roles in astrocytoma-susceptibility syndromes. The chromosomal region 9q34 (site of TSC1) appeared to be under-represented in 25% of the tumours, while 16pl3 (site of TSC2) was diminished in -38%. Similarly, loci for NF1 and NF2 were involved in aberrations in -10% and 38% of the cases respectively, as were those of PMS2 (22%), APC (19%) and a number of miss- I Cytogenetic Analysis of DNA Copy Number Aberrations in High Malignancy Grade Astrocytomas match repair (MMR) genes. Eight tumours had probable loss at lp36. Several novel locations were also suggested An attempt to correlate DNA copy number alterations with survival showed that among patients with grade IV tumours, there were on average far fewer chromosome aberrations per tumour in four of the five patients surviving longer than one year after diagnosis than in those who died before this. There was some suggestion of a worse prognosis in Grade IV tumours with a specific deletion of lp36, which would agree with a previous report. The only Grade IV tumour that was studied by all three approaches showed good agreement between array and metaphase CGH. In addition, array CGH revealed small regions of loss in the region of PTEN (CHR lOq) and TP53 (CHR 17p) below the resolution of the metaphase CGH. The M-FISH revealed very large numbers of chromosomes and several translocations, and comparison of the microarray data and the MFISH data suggests possible candidate regions for breakpoints. The data are discussed in the light of previous work and with a view to the possibility that there may be some diversity in the cellular origin of astrocytomas and that haploinsufficiency may play some role in oncogenesis.

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