Tumour heterogeneity and evolutionary dynamics in colorectal cancer

Abstract

Colorectal cancer (CRC) has a global burden of disease. Our current understanding of CRC has progressed from initial discoveries which focused on the stepwise accumulation of key driver mutations, as encapsulated in the Vogelstein model, to one in which marked heterogeneity leads to a complex interplay between clonal populations. Current evidence suggests that an initial explosion, or "Big Bang", of genetic diversity is followed by a period of neutral dynamics. A thorough understanding of this interplay between clonal populations during neutral evolution gives insights into the roles in which driver genes may participate in the progress from normal colonic epithelium to adenoma and carcinoma. Recent advances have focused not only on genetics, transcriptomics, and proteomics but have also investigated the ecological and evolutionary processes which transform normal cells into cancer. This review first describes the role which driver mutations play in the Vogelstein model and subsequently demonstrates the evidence which supports a more complex model. This article also aims to underscore the significance of tumour heterogeneity and diverse clonal populations in cancer progression.

Fig. 1. Representative dendrogram showing differences in the distribution of mutations in premalignant lesions, and cancer.

In (a) premalignant lesions, the trunk tends to be shorter with multiple branches, suggesting the presence of multiple subclones. In (b) cancer, the trunks are longer, demonstrating that cancer cells tend to be clonal. These dendrograms are adapted from Cross et al. [43].

Fig. 2. Two different evolutionary models are presented here, with each colour representing a subclonal population.

In (a) the big bang model, multiple subclonal populations are seen early and followed by a period of neutral evolution. In (b) the Darwinian model, subclones with a selective advantage outgrow other subclones.