Aneuploidy and complex genomic rearrangements in cancer evolution

Abstract

Mutational processes that alter large genomic regions occur frequently in developing tumors. They range from simple copy number gains and losses to the shattering and reassembly of entire chromosomes. These catastrophic events, such as chromothripsis, chromoplexy and the formation of extrachromosomal DNA, affect the expression of many genes and therefore have a substantial effect on the fitness of the cells in which they arise. In this review, we cover large genomic alterations, the mechanisms that cause them and their effect on tumor development and evolution.

Figure 1. The effect of selective and physical considerations on alteration frequencies.

a, An illustration of three arbitrary alterations with different rates of formation and selective advantage. b, Illustration of the impact of both physical and selective effects on the observed frequencies of large-scale genomic alterations. Alterations with a high formation rate due to physical effects will occur frequently in individual tumor cells, however, a positive selective impact is needed for cells with the alterations to expand relative to non-altered tumor cells. Alteration A will occur more often than other alterations in individual tumor cells, but will not expand due to its reduced fitness. Alterations B and C arise at a similar rate, but B is able to expand much more than C due to the large fitness increase it confers.

Figure 2. Causes of whole genome duplication and links between complex genomic events.

a, Cytokinesis failure during mitosis can result in binucleation, and genome duplicated cells in subsequent cell divisions. b, Mitotic slippage is a process where mitotic arrest can result in the cell skipping mitosis. c, Two tumor cells or a tumor and healthy cell can fuse to form a genome duplicated tumor cell. d, Schematic showing how a lagging chromosome event can cause aneuploidy as well as lead to the formation of micronuclei along with broken bridge chromosomes.

Figure 3. A summary of the processes underlying four classes of large-scale genomic rearrangements.

a, Chromoplexy arises through translocations involving multiple chromosomes, generating apparent chains of rearrangements. b, In chromothripsis, chromosomes are shattered and near-randomly rejoined in a single event. c, Breakage-fusion-cycles are initiated by fusion of two sister chromatids, generating a dicentric chromosome. This chromosomal bridge breaks during the subsequent anaphase, resulting in double strand DNA breaks which may trigger further cycles. d, Seismic amplifications represent a combination of previously-described rearrangement events, whereby chromothripsis is followed by amplification through ecDNA formation.