Jonathan D. Towler

Colorectal cancer (CRC) develops through evolutionary processes involving genomic alterations, epigenetic regulation, and microenvironmental interactions. While traditionally explained by the stepwise accumulation of driver mutations, contemporary evidence supports a ‘Big Bang’ model in which many early-arising clones expand simultaneously to establish extensive heterogeneity. We reviewed recent studies employing spatially resolved multi-omic sequencing of tumour glands combined with computational modelling. These approaches enable high-resolution reconstruction of clonal architecture, transcriptional states, and chromatin accessibility. Findings show that although early clonal mutations shape tumour expansion, gene expression variability can be independent of genetic ancestry and instead reflects phenotypic plasticity driven by microenvironmental cues. Epigenomic analyses identified recurrent somatic chromatin accessibility alterations in promotors and enhancers of oncogenic pathways, frequently in the absence of DNA mutations, suggesting alternative mechanisms of gene regulation. Immune-focused studies demonstrated that early silencing of antigen-presenting genes and loss of neoantigens facilitate immune escape despite active surveillance. CRC is shaped by an interplay of genome, epigenome, and immune evolution, with non-genetic mechanisms and tumour plasticity emerging as important drivers of progression and therapeutic resistance.