Most solid tumors are characterized by abnormal chromosome numbers (aneuploidy) and karyotypic profiling has shown that the majority of these tumors are heterogeneous and chromosomally unstable. Chromosomal instability (CIN) is defined as persistent mis-segregation of whole chromosomes and is caused by defects during mitosis. Large-scale genome sequencing has failed to reveal frequent mutations of genes encoding proteins involved in mitosis. On the contrary, sequencing has revealed that most mutated genes in cancer fall into a limited number of core oncogenic signaling pathways that regulate the cell cycle, cell growth, and apoptosis. This led to the notion that the induction of oncogenic signaling is a separate event from the loss of mitotic fidelity, but a growing body of evidence suggests that oncogenic signaling can deregulate cell cycle progression, growth, and differentiation as well as cause CIN. These new results indicate that the induction of CIN can no longer be considered separately from the cancer-associated driver mutations. Here we review the primary causes of CIN in mitosis and discuss how the oncogenic activation of key signal transduction pathways contributes to the induction of CIN.

The terms 'haploid' and 'diploid' that describe single (n) and double (2n) chromosome sets in cells were coined by the Polish-German botanist Eduard Strasburger and originate from the Greek terms haplóos meaning 'single' and diplóos meaning 'double'. The term 'ploidy' was subsequently derived to describe the total chromosome content of cells. Consequently, the term 'euploid' refers to a chromosome complement that is an exact multiple of the haploid number. Therefore, haploids and diploids are both cases of normal euploidy. Euploid types that have more than two sets of chromosomes are 'polyploid' such as 'triploid' (3n), 'tetraploid' (4n), 'pentaploid' (5n), and so forth. There are various natural euploid states with some organisms existing as haploids (fungi), diploids (most mammals), and polyploids (plants).Cells rely on precise mechanisms to ensure accurate chromosome segregation during mitosis and meiosis to maintain their euploid state. Errors in the faithful execution of these mechanisms cause chromosome mis-segregation resulting in the generation of 'aneuploid' (i.e. 'not euploid') daughter cells. Aneuploidy is defined as a chromosome number that deviates from a multiple of the haploid set, and it is associated with abnormalities in cell function, such as in cancer and in organismal development such as in Down syndrome and mosaic variegated aneuploidy (MVA) (Figure 1). Aneuploidy reflects both gains/losses of whole chromosomes, leading to 'whole chromosomal' aneuploidy, as well as non-balanced rearrangements of chromosomes, including deletions, amplifications or translocations of large regions of the genome resulting in 'structural' aneuploidy. Here, we discuss the causes of aneuploidy (Figure 2) and the consequences of aneuploidy on cells and organisms.

Summary Karyotype diversity is a hallmark of solid tumors that contributes to intratumor heterogeneity. This diversity is generated by persistent chromosome mis-segregation associated with chromosomal instability (CIN). CIN correlates with tumor relapse and is thought to promote drug resistance by creating a vast genomic landscape through which karyotypically unique clones survive lethal drug selection. We explore this proposition using a small molecule (UMK57) that suppresses chromosome mis-segregation in CIN cancer cells by potentiating the activity of the kinesin-13 protein MCAK. Sub-lethal doses of UMK57 destabilize kinetochore-microtubule (k-MT) attachments during mitosis to increase chromosome segregation fidelity. Surprisingly, chromosome mis-segregation rebounds in UMK57-treated cancer cells within a few days. This rapid relapse is driven by alterations in the Aurora B signaling pathway that hyper-stabilize k-MT attachments, and is reversible following UMK57 removal. Thus, cancer cells display adaptive resistance to therapies targeting CIN through rapid and reversible changes to mitotic signaling networks.