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Title: Genomic instability in sporadic colorectal cancer
Author: Curtis, Lucy Jane
Awarding Body: University of Edinburgh
Current Institution: University of Edinburgh
Date of Award: 1998
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This thesis has examined aspects of two forms of instability prominent in sporadic colorectal cancer, microsatellite instability (MSI) and chromosomal instability. Microsatellite instability describes a phenotype in which mutation of microsatellite sequences is widespread, probably due to defects of components of the mismatch repair pathway. Clonal chromosomal abnormalities, frequently observed in sporadic colorectal cancer, probably arise because of instability at the chromosomal level, and there is substantial, though not conclusive, evidence that they may result from defects of the p53 protein. Several lines of evidence suggest that chromosomal instability and defects of p53 may represent a mechanism, or mechanisms, of tumourigenesis distinct from that driven by defects of mismatch repair system. In this project, a series of experiments were undertaken to investigate the microsatellite instability phenotype, its possible cause, and the extent to which it coexists and interacts with chromosomal instability and p53 abnormalities. MSI was examined in a large population of sporadic human colorectal cancers and related to clinical and pathological tumour features in order to define traits which may suggest a distinct biological basis. Such instability was found to confer significant survival advantage, and to be inversely related to abnormality of the p53 protein, supporting the notion that these defects represent distinct tumorigenic pathways. In an attempt to discover the cause of microsatellite instability, mutation analysis of a likely candidate gene, hMSH2, was undertaken in selected case. This analysis yielded few exonic gene mutations supporting data from other studies which suggest that hMSH2 is not an important cause of the MSI phenotype in sporadic colorectal cancer. To further investigate the MSI phenotype, the behaviour of stable and unstable microsatellites over a period of time was examined through use of a series of xenografted human cancers. This demonstrated maintenance of the primary tumour phenotype in all xenografts over several months' passage in vivo, adding weight to the argument that microsatellite instability is persistent and is driven by an underlying retained defect.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available