Evolutionary dynamics in pre-invasive neoplasia

Abstract

Mutational processes occur in normal tissues from conception throughout life. Field cancerization describes the preconditioning of an area of epithelium to tumor growth. Pre-invasive lesions may arise in these fields, however only a minority of pre-invasive neoplasia progresses to overt malignancy. Within this review we discuss recent advances in our understanding of genomic instability processes in normal tissue, describe evolutionary dynamics in pre-invasive disease and highlight current evidence describing how increasing genomic instability may drive the transition from pre-invasive to invasive disease. Appreciation of the evolutionary rulebooks that operate in pre-invasive neoplasia may facilitate screening strategies, risk-stratification of pre-invasive lesions and precipitate novel preventative treatments in at-risk patient populations.

Keywords: Intratumor heterogeneity; cancer evolution; field cancerization; genomic instability; pre-invasive neoplasia.

Figure 1. Evolutionary dynamics of ongoing mutational processes contributing to the development of neoplasia.

From conception, mutational processes contribute to the acquisition of passenger and driver mutations. This leads to the expansion of clonal populations within histologically normal-appearing tissue. Nevertheless, due to tumor-suppressive factors, most clonal populations are unable to progress toward genomic instability, occupying a relative “evolutionary cul-de-sac”. Through transcriptional reprogramming and loss of tumour suppressor genes, some clones do progress and acquire the capability to tolerate extensive levels of genomic instability. This increases the evolutionary tempo which eventually enables the acquisition of an invasive and metastatic phenotype. Please note that the timescale is not proportional.