Abstract
Accurate identification of prognostic features to improve patient stratification and provide tailored disease management plans within early stage colorectal cancer (CRC) are essential to improve patient outcomes. This is particularly important given the increased number of early stage patients being diagnosed since the introduction of the bowel cancer screening programme. One such poor prognostic feature is tumour budding (TB), which will form the basis of the research within this thesis.TB is the histological manifestation of local tumour cell dissemination, observed at the tumour invasive front, and despite being an established prognostic marker, inconsistent definitions and reporting guidelines have hindered routine use. To improve TB detection and enumeration, a semi-automated classifier was developed, which compared favourably to a series of established manual methods, offering a freely available, rapid and transparent tool for TB assessment (Chapter 3). The TB classifier was independently validated within a novel cohort of pT1 tumours (n = 249), which represent a highly relevant setting, given that TB severity correlates to the presence of lymph node metastatic disease (Chapter 4). Following identification, the next step was to understand the molecular phenotype of a bud (Chapter 5). However, transcriptional characterisation of epithelial cells within a bud revealed a potential stroma confounding effect, due to limitations in the specificity of currently used isolation methodologies. Understanding the extent of this effect, within bud profiling studies and more broadly across transcriptional research, formed the basis of Chapter 6.
Overall, work within this thesis presents new understanding within two key areas, namely; 1) the histological identification of TB, and 2) the stroma confounding effect within transcriptional analyses. Taken together, this thesis represents an initial step towards a more accurate interpretation of the biological signalling underpinning TB, which may ultimately be used as a template for the development of tractable biomarkers and potential therapeutics targeting.
Thesis is embargoed until 31 July 2028.
| Date of Award | Jul 2023 |
|---|---|
| Original language | English |
| Awarding Institution |
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| Sponsors | Musgrave Scholarship |
| Supervisor | Philip Dunne (Supervisor), Daniel Longley (Supervisor) & Maurice Loughrey (Supervisor) |
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