Molecular risk stratification in early cancers detected during bowel cancer screening

However, many patients are stratified as high-risk, only to be found to have no LNM when surgery is performed, meaning they are unnecessarily exposed to surgical risks. To address this, this project aimed to identify molecular features associated with LNM status in T1 CRC, offering a potential avenue for more accurate risk stratification.<br><br>As this project aimed to employ gene signatures, first, some challenges associated with gene signature application were explored, with commonly used gene signatures found to be confounded by tumour composition (Chapter 3) and RAS-related gene signatures found to have limited association with KRAS mutational status in established human CRC (Chapter 4).

Then, using a cohort of T1 CRCs (n=230), the existing histopathology-based approach to T1 risk stratification was shown to lack specificity (Chapter 5). Finally, transcriptional profiling and <i>in silico</i> analysis of the same T1 cohort found no transcriptional features or signatures that could reliably discriminate between LNM-positive and LNM-negative T1 CRC (Chapter 6).<br><br>In summary, this work highlights the potential for misinterpretation of gene signatures and suggests that transcriptional features cannot reliably discriminate between LNM-positive and LNM-negative T1 CRC.<br><br><i>Thesis is embargoed until 31 July 2030.</i><br>