Fig. 5.

P53 as a gatekeeper for aneuploidy. In healthy cells (A), aneuploidy-induced stresses activate a p53 response, which prevents the propagation of aneuploid cells and causes their cell cycle arrest or death. In cancer cells, however, aneuploidy as well as p53 mutations are highly prevalent. In p53 mutant cancer cells (B) (~ 41% with TP53 gene mutations) (Hoadley et al. 2014), aneuploid cells can proliferate with low/moderate levels of aneuploidy. Propagation of replication stress, for example, can induce DNA damage and consequently further promote CIN. This leads to increased heterogeneity, which enables selection of optimal karyotypes. Approximately 59% of tumors are WT for p53 (C). In these tumors, aneuploidy can still be propagated by either developing mechanisms to surpass p53 activation (e.g., cyclin D1/2 upregulation in WGD) or by upregulating mechanisms to prevent accumulation of genomic instability (GIN) (e.g., upregulate DNA damage response pathways). As a result, such cells are more likely to accumulate numerical CNAs (nCNAs), mostly gains, while cells with structural CNAs (sCNAs) and/or monosomies are probably eliminated or overtaken by cells with more beneficial karyotypes