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Mechanisms of colorectal tumorigenesis associated with Mut-Y (MYH) deficiency and identification of novel predisposition genes in the multiple adenoma phenotype.

Thirlwell, C.; (2006) Mechanisms of colorectal tumorigenesis associated with Mut-Y (MYH) deficiency and identification of novel predisposition genes in the multiple adenoma phenotype. Doctoral thesis , University of London. Green open access

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Abstract

The main subjects of my thesis can be divided into three related areas. Firstly, determination of the mechanisms of tumoriogenesis associated with a recently identified, recessively inherited syndrome, AfrTZ-associated polyposis (MAP). MAP results from defective base excision repair (BER) caused by bi-allelic germline mutations in the human Mut-Y homologue (MUTYH, MYH) and leads to the development of colorectal adenomas and cancer. My work includes: further characterisation of the MAP phenotype completion of screening for mutations in other BER enzymes (OGG1 and MTH1) in individuals with multiple colorectal adenomas determination of the genetic pathway(s) involved in MAP tumorigenesis through studying loss of heterozygosity (LOH) and chromosomal abnormalities with array comparitive genomic hybridisation. A mouse model of MAP was developed as part of this thesis in order to study the development of intestinal adenomas from their earliest stages, and to evaluate the impact of environmental modification and chemopreventative therapies. Secondly, I determined to identify novel predisposition genes for the multiple adenoma phenotype. Up to fifty percent of individuals with multiple (5-100) colorectal adenomas (MCRAs) have no germline mutation in known predisposition genes (APC and MYH), but probably have a genetic origin. In these cases I determined to identify novel predisposition genes for the MCRA phenotype utilising various techniques. These included somatic screening of the adenomas for mutational signatures, expression array analysis of lymphoblastoid cell lines from these individuals and candidate gene approaches. Finally, I investigated the clonal origins of colorectal adenomas through studying adenomas from familial adenomatous polyposis (FAP), attenuated FAP (AFAP) and sporadic cases. In this thesis I developed a novel technique which utilises somatic APC mutations as clonal markers. This approach found 100% of FAP adenomas to be polyclonal and 100% of AFAP adenomas to be clonal in their origin.

Type: Thesis (Doctoral)
Title: Mechanisms of colorectal tumorigenesis associated with Mut-Y (MYH) deficiency and identification of novel predisposition genes in the multiple adenoma phenotype.
Identifier: PQ ETD:591341
Open access status: An open access version is available from UCL Discovery
Language: English
Additional information: Thesis digitised by ProQuest. Third party copyright material has been removed from the ethesis
UCL classification: UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute > Research Department of Oncology
URI: https://discovery.ucl.ac.uk/id/eprint/1444048
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