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Clinical and organoid studies of inherited polyposis syndromes

Truscott, Rebekah 2023. Clinical and organoid studies of inherited polyposis syndromes. PhD Thesis, Cardiff University.
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Duodenal disease is a significant cause of morbidity for Familial adenomatous polyposis (FAP) and MUTYH-associated polyposis (MAP) patients. The Spigelman staging system was developed in FAP to determine cancer risk and surveillance intervals and is also employed in MAP. No effective chemopreventions exist for both syndromes, and available pre-clinical models have limited recapitulation of disease. Using genotype and prospectively collected endoscopic data, this thesis addresses gaps in knowledge about the natural history of duodenal disease in MAP. This data demonstrates the duodenal disease phenotype in MAP is distinct from FAP: low adenoma multiplicity is observed, stage IV disease and cancer development are infrequent and 42.9% of high-grade dysplasia adenomas are <10mm in size. Risk of adenoma development is dependent on genotype. Findings suggest Spigelman staging-determined surveillance is inappropriate for cancer prevention in MAP, and an alternative scoring system should be considered. This is the largest study of adenoma and normal-mucosal small intestinal patient derived organoids (PDOs) reported (N=37). Genetic, histological and functional characterisation of several PDOs (N=12) showed PDOs are representative of interpatient heterogeneity and retain some characteristics of the tissue they were derived from. Using known chemotherapeutic agents, the study demonstrates these PDOs are a good in vitro drug testing platform: PDOs produced a clinically relevant response functionally, morphologically and at transcriptomic level after treatment. Translational readthrough drugs (TRIDs) were trialled in small intestinal FAP (N=3) and sporadic colorectal cancer PDOs (N=4) harbouring nonsense mutations, to determine their efficacy as APC nonsense suppression therapies. TRIDs had limited effect on APC protein restoration in PDOs in this study. However, PDOs established in this study present a promising in vitro personalised model of disease to identify novel chemotherapies in polyposis syndrome patients. More appropriate management of upper GI disease and effective chemopreventions in polyposis syndromes, should improve patient outcomes in the future.

Item Type: Thesis (PhD)
Date Type: Completion
Status: Unpublished
Schools: Medicine
Date of First Compliant Deposit: 18 January 2024
Last Modified: 02 Feb 2024 13:10

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