| Summary: | <p>Cancer has long been considered to be a disease driven by mutation. In recent years, this theory has been updated to reflect increased understanding of the importance of additional factors influencing disease pathogenesis, such as the cell of origin and microenvironment. In this thesis, I explore somatic mutation acquisition and the effect of microenvironmental influence on human and animal models of colorectal tumourigenesis.</p>
<p>Analysis of mutations in healthy human colonic epithelium revealed a capacity to tolerate driver mutations, while inflamed epithelium exhibited increased mutation acquisition. I also investigated somatic mutation following exposure to the mutagen AOM in mice harbouring spontaneous colitis or a constitutively deranged intestinal microenvironment. Here, I show that these differences in underlying disease state influence mutation acquisition and provide novel evidence of an AOM-associated mutational signature in mice.</p>
<p>Although numerous studies have suggested links between morphogenetic signalling pathways and the DNA damage response (DDR), the influence of these pathways upon mutation protection mechanisms within the intestine remains unclear. To explore this, I studied the Vil1-Grem1 (VG) mouse, a model of disrupted intestinal homeostasis in which aberrant epithelial expression of the BMP signalling antagonist Grem1 results in the formation of ectopic crypts. I provide evidence of impaired activation of DDR pathways within ectopic crypts following exposure to ionising radiation and go on to propose that a novel mechanism linking BMP signalling and DNA repair results in increased genomic instability within this compartment.</p>
<p>I also examined the effect of therapeutic restoration of cell fate determination on mutation acquisition following AOM exposure in VG mice. I demonstrate that therapeutic restoration of morphogen gradients in VG mice can rescue disease phenotype and confer protection against mutation acquisition, but may also result in a putative skew to DNA repair-associated mutation acquisition in these mice.
Finally, I provide evidence that disease progression in an immune-deficient model of inflammation-associated cancer occurs in the absence of mutation accumulation and is instead associated with dysregulated gene expression. Importantly, I demonstrate that abrogation of the inflammatory drive within this model rescues disease phenotype in colitis but not in polyps.</p>
<p>Overall, I have demonstrated that somatic mutation acquisition within the intestine varies and reflects the influence of the microenvironment, cell of origin and mutation protection mechanisms upon disease pathogenesis. This has translational relevance, given that the development of personalised therapies requires a holistic and accurate understanding of the mechanisms underpinning the vast heterogeneity of colorectal cancer.</p>
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