Telomeres are specialised structures that that cap the ends of chromosomes; and prevent the natural end of a chromosome from being recognised as a double stranded DNA break. Telomeres erode with ongoing cell division ultimately leading the induction of replicative senescence that provides a proliferative lifespan barrier. In the absence of a functional DNA damage response, telomeres are prone to end-fusions, creating dicentric chromosomes that can initiate breakage fusion–bridge cycles. Evidence from studies in well-defined mouse models of cancer, and also human tumours, have shown that telomere dysfunction may be a key event in the progression of disease via the increasing genomic instabilities that arise from telomere fusion events. The key aim of this thesis was to test the hypothesis that telomere dysfunction occurs during the progression of breast cancer and that this can drive the large-scale genomic rearrangement frequently observed in this disease. Technology development was attempted in the hope to allow single-molecule telomere fusion detection of more complex mutational structures, with limited success but possible future potential. Telomere length analysis was carried out using high resolution single molecule PCR strategies (STELA) in a panel of DNA samples derived from invasive ductal carcinoma. Telomere length data analysed alongside clinical data received for all samples was used for the potential utility of telomere length as a potential prognostic indicator in breast cancer. A key finding of this work was to demonstrate the use STELA combined with statistical tests to show that short telomere length is highly significant in terms of prognosis in breast cancer. Telomere length stratification could thus potentially be used as a method of defining new breast cancer subtypes in terms of severity.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:571744 |
| Date | January 2013 |
| Creators | Simpson, Katherine |
| Publisher | Cardiff University |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | http://orca.cf.ac.uk/47310/ |
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