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Genetic mechanisms in colorectal polyposis

Short, Emma 2018. Genetic mechanisms in colorectal polyposis. PhD Thesis, Cardiff University.
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Individuals with >/= 10 colorectal adenomas have traditionally been referred for genetic testing to identify APC and MUTYH mutations which cause Familial Adenomatous Polyposis (FAP) and MUTYH-Associated Polyposis (MAP) respectively. Mutations are found in most patients with >100 adenomas but in only a minority of those with 10-100 adenomas. The research described in this thesis focuses on polyposis patients with ‘no mutation identified’ (NMI). The aim of this project was to identify novel genetic mechanisms causing polyposis in a cohort of 60 unrelated NMI patients. Genetic variants were sought outside of the open reading frames of APC and MUTYH, at a low frequency in APC, in other known and candidate ‘polyposis genes’ and in whole exomes. Novel variants were characterised genetically and functionally to provide evidence for or against their clinical significance. Rare variants were found in the 5’UTR of APC, the mismatch repair (MMR) genes, POLE, POLD1 and AXIN2. The 5’UTR APC variant, c.-190A>G, was associated with reduced transcript levels and segregated with FAP in a multiplex family, allowing translation to diagnostic testing. Three additional patients had reduced APC transcript levels, but the cause was not determined by deep sequencing of their genomic APC loci. The MMR gene variants were deemed unlikely to be pathogenic as associated tumours were microsatellite stable with normal MMR protein immunohistochemistry. Studies into the pol gene variants are ongoing. The AXIN2 mutation, c.1642G>T, p.Glu548*, was identified in a family with polyposis and ectodermal dysplasia. Most of their adenomas appeared to lack APC mutations and in vitro studies suggested that the mutation may impair inhibition of Wnt-signalling. Gene panel testing using next-generation sequencing technologies may improve molecular genetic diagnosis of previously NMI patients but additional characterisation of novel variants is likely to be required for clinical translation, with the ultimate aim of preventing colorectal cancer.

Item Type: Thesis (PhD)
Date Type: Completion
Status: Unpublished
Schools: Medicine
Date of First Compliant Deposit: 15 October 2018
Last Modified: 05 Aug 2022 01:35

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