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An investigation into mechanisms of tumourigenesis in the intestine of novel Apc mutant mice and in the small bowel of humans with Familial Adenomatous Polyposis

Deheragoda, M.G.; (2010) An investigation into mechanisms of tumourigenesis in the intestine of novel Apc mutant mice and in the small bowel of humans with Familial Adenomatous Polyposis. Doctoral thesis, UCL (University College London). Green open access

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Abstract

This thesis examined the mechanisms underlying small intestinal tumourigenesis in experimental models and humans with a mutation in the Adenomatous Polyposis Coli gene. Mutant APC alleles found in human intestinal carcinomas retain two 20 amino acid repeats (20AARs), required for beta catenin binding. Current APC mutant experimental model systems do not contain mutant APC proteins analogous to those found in human disease. I therefore generated and characterised a novel model of intestinal tumourigenesis in order to evaluate the effect of two 20AARs on optimal levels of nuclear beta catenin required for tumourigenesis. I developed a further model in order to examine the role of the C terminus of APC in intestinal tumourigenesis. I found that two 20AARs generated an intermediate level of nuclear beta catenin which was optimal for tumourigenesis and the N terminus alone was sufficient for tumourigenesis. The presence of two 20AARs conferred a more severe phenotype than models with zero 20AARs. An increase in the stem cell number and a high crypt fission index accounted for the observed difference in severity. I extended these findings to patients with duodenal Familial Adenomatous Polyposis (FAP) and found increased stem cell numbers and a high crypt fission index in these patients compared with patients without APC mutations. I examined normal human duodenum and found that niche succession, monoclonal conversion and crypt fission led to the spread of mutant clones in intestinal mucosa, using mitochondrial DNA analysis.

Type:Thesis (Doctoral)
Title:An investigation into mechanisms of tumourigenesis in the intestine of novel Apc mutant mice and in the small bowel of humans with Familial Adenomatous Polyposis
Open access status:An open access version is available from UCL Discovery
Language:English
UCL classification:UCL > School of Life and Medical Sciences > Faculty of Medical Sciences > Wolfson Institute and Cancer Institute Administration > Cancer Institute > Research Department of Pathology

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