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The molecular mechanisms of duodenal tumourigenesis in familial adenomatous polyposis (FAP) and MUTYH-associated polyposis (MAP)

Meuser, Elena 2018. The molecular mechanisms of duodenal tumourigenesis in familial adenomatous polyposis (FAP) and MUTYH-associated polyposis (MAP). PhD Thesis, Cardiff University.
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Duodenal disease has become a leading cause of morbidity and mortality for patients with the inherited syndromes familial adenomatous polyposis (FAP) and -associated polyposis (MAP), yet its underlying mechanisms remain understudied and insufficiently understood. This thesis seeks to address gaps in the current knowledge of duodenal tumourigenesis in both disorders. APC mutations were confirmed as early events in duodenal tumourigenesis in FAP duodenal adenomas (n=56) and, for the first time, in MAP duodenal adenomas (n=31). Biallelic somatic mutations in MAP duodenal polyps recapitulated the germline-somatic pattern characteristic of FAP adenomas. Compared to colorectal lesions, duodenal adenomas showed a 3’ shift in mutational clustering, suggesting different WNT signalling requirements between the two organs. Whole exome sequencing of 49 duodenal adenomas (FAP n=25, MAP n=24) revealed a higher burden of somatic mutations in MAP than similarly sized FAP duodenal adenomas, despite lower Spigelman stage disease in the MAP patients studied. KRAS mutations were identified in 13/24 MAP adenomas vs 2/25 FAP adenomas (P=0.0015). MAP adenomas appear more likely to show high-risk molecular characteristics. Novel potential drivers of duodenal tumourigenesis were also identified. Whole transcriptome sequencing was performed on 44 duodenal adenomas (FAP n=29, MAP n=15) and 23 duodenal normal mucosa (FAP n=15, MAP n=8). Distinct gene expression profiles were found in FAP and MAP duodenal adenomas. Paralleling the exome sequencing results, MAP adenomas displayed higher degrees of molecular re-modelling, with implications for the speed of tumour progression. Irrespective of disease context, the presence of mutations in a novel driver gene was associated with transcriptional deregulation of membrane-bound molecules. The identification of novel drivers and commonly deregulated pathways contributes to our understanding of tumourigenesis in FAP and MAP. The data presented here may provide a first step towards novel opportunities for targeted prevention and treatment for FAP and MAP duodenal disease.

Item Type: Thesis (PhD)
Date Type: Completion
Status: Unpublished
Schools: Medicine
Date of First Compliant Deposit: 18 February 2019
Last Modified: 15 Feb 2020 03:05

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