Most solid tumors are aneuploid and many mis-segregate chromosomes at very high rates in a phenomenon termed chromosomal instability (CIN). Aneuploidy is a state in which the number of chromosomes in a cell or organism deviates from multiples of the haploid number of chromosomes. Chromosomal instability (CIN) is defined as a persistently high rate of loss and gain of whole chromosomes. For the purpose of this review, we adhere to the strict definition of CIN as whole chromosome mis-segregation and do not include structural rearrangements of chromosomes (translocations, deletions, inversions), although these structural rearrangements may also be linked to mis-segregation.
Aneuploidy was first associated with tumors in the late 19th
century. In 1890, David von Hansemann examined tissue sections from epithelial tumors and discovered cells that were going through multipolar divisions as well as bipolar yet asymmetric divisions of chromosomes [1
]. Subsequently, Theodor Boveri compared defects in sea urchin embryos that had gone through multipolar divisions and proposed that a “certain abnormal chromatin constitution”, regardless of how it originated, “would result in the origin of a malignant tumor” [2
]. The consequence of CIN is aneuploidy but the line between aneuploidy and CIN was blurred in these early studies because tools were not available to discriminate between aneuploidy (a state that describes the cellular karyotype) and CIN (increased rates of chromosome mis-segregation). This distinction is important because aneuploidy can arise in different ways; however, the fact that the majority of aneuploid tumors have chromosome numbers within the range of diploid cells — i.e. 40–60 chromosomes (http://cgap.nci.nih.gov/Chromosomes/Mitelman
; also see [3
]) — indicates that the accumulation of chromosome imbalances generated by the sequential loss and gain of single chromosomes through CIN may be the most common pathway to aneuploidy. Because aneuploidy represents a state of having an abnormal number of chromosomes and CIN is a condition of an increased rate of chromosome mis-segregation, the criteria needed to establish each condition are different. Aneuploidy can be detected by any method that quantifies chromosome numbers, including karyotype analysis, fluorescence in situ
hybridization, spectral karyotyping, or array-based comparative genomic hybridization analyses. However, by themselves, these techniques are not sufficient to yield quantitative measures of CIN. Detection of CIN requires the determination of chromosome mis-segregation rates [4
], which can be achieved by coupling tools for counting chromosomes with clonal cell assays that allow the analysis of chromosomal variation in the resulting clonal population. In these assays, populations of cells derived from chromosomally stable precursors will show little variation in chromosome content (regardless of whether or not they are aneuploid); in contrast, cells in a population derived from a CIN precursor cell will show high levels of deviance in chromosome content.
Using this single-cell colony assay, Vogelstein and colleagues [5
] ignited research into the mechanisms underlying CIN when they demonstrated two key properties of colon cancer cell lines. First, they showed that colon cancer cells with microsatellite instability (MIN) maintain a stable chromosome content, but aneuploid colon carcinoma cells exhibited deviations from the modal chromosome number that ranged from 16% to 66%, indicating the presence of CIN. High deviations in chromosome content in clonal populations were subsequently reported in cells derived from many other tumor types, including breast and lung [6
], indicating that CIN is a general property of aneuploid cancer cells. Direct measurement of chromosome mis-segregation rates in CIN cancer cell lines has recently shown that these cells mis-segregate a chromosome, on average, once every one to five cell divisions [8
]. This may represent the upper limit of tolerable chromosome changes because massive chromosome mis-segregation caused by checkpoint failure [9
] or multipolar anaphase [11
] is lethal. Secondly, Vogelstein and colleagues [5
] showed that fusion of MIN and CIN cells resulted in hybrid cells that retained the CIN phenotype, suggesting that the underlying mechanisms that cause CIN behave as dominant traits.
Here, we discuss recent advances that illuminate the underlying mechanisms causing CIN in human tumor cells. These mechanisms reduce mitotic fidelity and include defects in chromosome cohesion, the spindle assembly checkpoint (SAC), centrosome copy number, kinetochore– microtubule attachment dynamics, and cell-cycle regulation. We further discuss how the knowledge gained by uncovering these mechanisms unveils strategies to exploit CIN to improve cancer therapy.