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Title: The short arm of chromosome 8 in breast cancer
Author: Cooke, S. L.
Awarding Body: University of Cambridge
Current Institution: University of Cambridge
Date of Award: 2008
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The aim of this project was to characterise the rearrangements of 8p in multiple tumours and identify recurrently targeted regions of distal 8p. Recurrent rearrangements were studied at high resolution to define the minimum common set of affected genes. A candidate gene analysis approach was applied to these genes to identify those under selection. The clinical relevance of genes identified by the initial survey on cell lines was verified in primary tumours by expression analysis and fluorescence in situ hybridisation on paraffin embedded tissue sections. Array CGH of forty-one cancer cell lines identified sections of 8p21.3, 8p22 and 8p23.3 as regions of interest containing six, three and four potential target genes respectively. 8p21.3 was the site of a novel amplicon which, although a relatively rare event, was seen in both cell lines and primary tumours. 8p22 was the site of multiple non-overlapping rearrangements suggesting that at two of the three affected genes could be cancer genes. 8p23.3 was frequently lost as a result of homozygous and heterozygous terminal or interstitial deletions. Expression studies of the genes in this region, in both cell lines and primary tumours, suggested ARHGEF10 as a candidate tumour suppressor gene. Mutation screening of the remaining copy of ARHGEF10 in a cell line with a heterozygous deletion found a single base change, not listed as a single nucleotide polymorphism, which results in a non-conservative substitution in a highly conserved region of the protein. Although the overall pattern of changes on 8p is complex and variable, this can be explained by the high density of target genes on this chromosome arm. The consensus pattern, of translocation within 8p12 and distal loss, is potentially therefore driven by the loss of multiple tumour suppressor genes on distal 8p. More complex patterns of 8p rearrangement result form a combination of factors. Firstly, these genes being targeted by separate events within a single tumour, and secondly, each gene only being targeted in a small percentage of tumours.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available