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Title: Mechanisms of intestinal tumorigenesis resulting from APC mutations
Author: Segditsas, Stefania
ISNI:       0000 0004 2676 114X
Awarding Body: University College London (University of London)
Current Institution: University College London (University of London)
Date of Award: 2008
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Colorectal cancer typically arises through the sequential accumulation of mutations in different genes. Mutations in the adenomatous polyposis coli (APC) gene are thought to be the initiating step in this sequence of events and are found in the majority of early colorectal tumours. Investigation of these lesions has revealed that selection of 'optimal' combinations of mutations at the APC locus is in place, but the roles of such selected combinations have never been clarified. In the work presented in this thesis, I have demonstrated that similar constraints on APC mutations are active in tumours from attenuated FAP (AFAP) patients and that given the sub-optimal location of the germline APC mutation in these patients, additional somatic mutations are often required, especially in patients with germline mutations in the alternatively spliced region of exon 9. I have also shown that APC promoter hypermethylation does not appear to play a fundamental role in the selection of optimal APC genotypes. I have shown that the optimum combinations of mutations at APC are those that allow retention of some APC activity with respect to β-catenin degradation and that this has effects on the resulting activation of the Wnt signalling pathway. Optimal combinations of APC mutations result in intermediate nuclear β-catenin levels, which surprisingly highly activate a selection of Wnt targets. In an attempt to identify novel Wnt targets that are important for tumorigenesis and could serve as therapeutic targets, I have validated results from a cross-species comparison that identified a set of genes showing consistent differential expression between early tumour samples carrying APC mutations and normal tissue. In addition, I have investigated the biological function of one such-identified molecule, the serum/glucocorticoid-regulated kinase (SGK1), and I have revealed its potential role as a key regulator of intestinal cell differentiation and apoptosis.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available