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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
Author: Deheragoda, M. G.
ISNI:       0000 0004 2727 727X
Awarding Body: University College London (University of London)
Current Institution: University College London (University of London)
Date of Award: 2010
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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.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available