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.