Causes and consequences of aneuploidy in cancer

Key Points Genomic instability, including whole-chromosome aneuploidy, is a hallmark of cancer. The disruption of multiple pathways, including defects in kinetochore–microtubule attachments and dynamics, centrosome number, spindle assembly checkpoint (SAC) and chromosome cohesion, can lead to aneuploidy. Aneuploidy is generally detrimental in non-transformed cells and can result in imbalances at the level of the transcriptome and proteome. A key question and area of research is how cells can adapt to tolerate aneuploidy. Aneuploidy can be an effective mechanism to generate phenotypic variation and adaptation under a selective pressure. Aneuploidy can both promote and inhibit tumorigenesis. Aneuploidy is a highly attractive target in cancer therapy. Therapeutics that target aneuploidy could either target aneuploidy generally or target specific recurrent aneuploidies that are associated with certain cancers. Aneuploidy — an abnormal number of chromosomes — typically has a detrimental effect on viability. Somewhat paradoxically, it is a remarkably common feature of cancer. This Review discusses how aneuploidy occurs, the cellular responses to aneuploidy and how aneuploidy can provide particular selective advantages during tumorigenesis. Genetic instability, which includes both numerical and structural chromosomal abnormalities, is a hallmark of cancer. Whereas the structural chromosome rearrangements have received substantial attention, the role of whole-chromosome aneuploidy in cancer is much less well-understood. Here we review recent progress in understanding the roles of whole-chromosome aneuploidy in cancer, including the mechanistic causes of aneuploidy, the cellular responses to chromosome gains or losses and how cells might adapt to tolerate these usually detrimental alterations. We also explore the role of aneuploidy in cellular transformation and discuss the possibility of developing aneuploidy-specific therapies.