Genomic heterogeneity in advanced colorectal cancer

Systemic chemotherapy is the primary treatment modality for metastatic colorectal carcinoma (MCRC). However, both conventional and novel chemotherapeutic drugs produce only modest improvements in outcome despite the introduction of predictive biomarkers. It is postulated that genomic heterogeneity within MCRC may be responsible for poor therapeutic response, but a comprehensive analysis of disseminated disease has not been performed. This thesis provides in-depth analysis of the clinicopathological and genomic features within a cohort of fatal MCRC cases recruited via the ‘Gift’ research autopsy project. Material sampled at autopsy was analysed at the allelic and chromosomal level using targeted and whole genome sequencing (WGS); the pattern of genomic change within and between deposits was correlated with that of any resected disease and the clinical data for each donor. The insights from this cohort were further explored within a series of locally advanced CRC using micro-dissection of intravascular, intraperitoneal and intranodal tumour deposits. Initial analysis demonstrated that mutation status at therapeutically predictive genomic loci is virtually homogenous within cases of disseminated MCRC. Phylogenetic analysis of WGS data documented the evolutionary and clonal complexity within MCRC, showing that, whilst clonal distribution may correlate with disease distribution, multiple clones from the same primary tumour may converge on the same metastatic site and demonstrate dissemination via similar metastatic routes. It was also demonstrated that most key genomic events arise early within the development of MCRC and when putative ‘driver’ events occur within established disease they do not appear to produce dominant metastatic clones. Therefore, it is concluded that, if a tumour has the capacity to metastasise, this characteristic is present across many or all subclones within a tumour and the likely determinant of the pattern of metastatic spread is a combination of the core biology of a tumour and the regional features of the surrounding bowel.