Fig. 9: Evolutionary dynamics of local sequence changes (single-nucleotide mutations, short sequence deletions/duplications) and chromosomal structural aberrations during esophageal cancer evolution.

Prior to p53 loss, the suppression of cell division after chromosome missegregation events or the acquisition of DNA damage inhibits clonal expansion of chromosomal structural alterations; therefore, only alterations that neither result from nor lead to chromosome missegregation or instability (local sequence changes, focal deletions/duplications, or uniparental disomies) are detectable at the clonal level. After p53 loss, there is a rapid increase of SCNA burden per cell that is due to both the clonal expansion of ancestral SCNAs generated by chromosome missegregation and secondary SCNAs accumulated during the downstream evolution of unstable chromosomes, the latter generating both copy-number heterogeneity and DNA duplications. Although the average mutational burden per cell (of both local and structural alterations) and the total genetic diversity of the tumor clone continue to increase during cell proliferation, the acquisition of cancer drivers can cause clonal dominance or sweep that make minor subclones harder to detect by bulk or even single-cell sequencing. Therefore, analyses of precancer lesions with limited clonal expansion can reveal ancestral genetic heterogeneity that may be undetectable in advanced cancers.