Chromosomal Instability as a Driver of Tumor Heterogeneity and Evolution

Abstract

Large-scale, massively parallel sequencing of human cancer samples has revealed tremendous genetic heterogeneity within individual tumors. Indeed, tumors are composed of an admixture of diverse subpopulations-subclones-that vary in space and time. Here, we discuss a principal driver of clonal diversification in cancer known as chromosomal instability (CIN), which complements other modes of genetic diversification creating the multilayered genomic instability often seen in human cancer. Cancer cells have evolved to fine-tune chromosome missegregation rates to balance the acquisition of heterogeneity while preserving favorable genotypes, a dependence that can be exploited for a therapeutic benefit. We discuss how whole-genome doubling events accelerate clonal evolution in a subset of tumors by providing a viable path toward favorable near-triploid karyotypes and present evidence for CIN-induced clonal speciation that can overcome the dependence on truncal initiating events.

Figure 1.

Chromosomal instability (CIN) in cancer. (A) Cancer cells experience frequent errors in the segregation of entire chromosomes, leading to karyotypic heterogeneity. Depending on the oncogenic and tumor suppressive effect of genes encoded by individual chromosomes, individual karyotypes will lead to distinct proliferative states and subclonal heterogeneity shaping the overall fitness of the population. Cell size depicts the relative cell fitness. Chromosomal instability (CIN) can enable rapid expansion of cells with variable fitness. (B) Lagging chromosomes during mitosis are a hallmark of CIN in cancer. They result from the erroneous attachments of chromosomes to spindle microtubules at the kinetochores. Most of the cellular defects that lead to CIN in cancer converge onto this process and produce lagging chromosomes.

Figure 2.

Experimental and computational work reveals a favorable near-triploid karyotype, which favors clonal fitness. Diploid-derived and tetraploid-derived populations alike can achieve this karyotype, albeit at a much lower fitness cost for the latter, suggesting that whole-genome doubling provides a more cost-effective path toward a highly favorable state.

Figure 3.

Diagram depicting the link between numerical and structural chromosomal instability (CIN). In addition to aneuploid karyotypes, chromosome segregation during mitosis also leads to the formation of chromosome-containing micronuclei. This in turn leads to pulverization of their enclosed chromosomes and persistence of DNA damage into the subsequent mitosis. Activation of a partial mitotic DNA damage response in turn leads to whole chromosome segregation forming a cycle linking numerical and structural CIN.

Figure 4.

Relative tumor clonal fitness as a function of chromosomal instability (CIN). Excessively low CIN would suppress genomic heterogeneity leading to reduction in tumor adaptability, whereas excessively high CIN would lead to genomic collapse, DNA damage, and frequent nullisomy events incompatible with viability.