Cancer karyotypes: survival of the fittest

Abstract

Cancer cells are typically characterized by complex karyotypes including both structural and numerical changes, with aneuploidy being a ubiquitous feature. It is becoming increasingly evident that aneuploidy per se can cause chromosome mis-segregation, which explains the higher rates of chromosome gain/loss observed in aneuploid cancer cells compared to normal diploid cells, a phenotype termed chromosomal instability (CIN). CIN can be caused by various mechanisms and results in extensive karyotypic heterogeneity within a cancer cell population. However, despite such karyotypic heterogeneity, cancer cells also display predominant karyotypic patterns. In this review we discuss the mechanisms of CIN, with particular emphasis on the role of aneuploidy on CIN. Further, we discuss the potential functional role of karyotypic patterns in cancer.

Keywords: CIN; aneuploidy; cancer; karyotype; selection.

Figure 1

The degree of aneuploidy directly correlates with CIN, as measured by analysis of anaphase lagging chromosomes. One way to measure CIN is by determining the rates of anaphase lagging chromosomes in dividing cells. In a normal anaphase, chromosomes are equally segregated to the two poles of the mitotic spindle, as illustrated by the diagram in (A). Some dividing cells display anaphase lagging chromosomes (B), single chromosomes that lag behind at the cell equator as all the other chromosomes move to the spindle poles. Anaphase lagging chromosomes are caused by merotelic kinetochore attachment (Cimini et al., 2001), a kinetochore mis-attachment in which a single kinetochore is bound to microtubules from two spindle poles instead of just one. (C) XY plot showing the relation between anaphase lagging chromosomes and modal chromosome number in various cell lines. The graph also shows linear fits and regression values (R²). The three colors refer to data sets from different labs: red is for data from the Cimini Lab [(Silkworth et al., 2009) and (Silkworth, Nardi, and Cimini, unpublished)]; blue is for data from the Pellman lab (Ganem et al., 2009); green is for data from the Compton lab (Thompson and Compton, 2008). Karyotype information for cell lines from the Cimini Lab and the Pellman Lab was obtained from The American Type Cell Culture website (ATCC). Karyotype information for cell lines from the Compton Lab is that reported in (Thompson and Compton, 2008). Although there is a general trend in which higher chromosome modal number correlates with higher rates of anaphase lagging chromosomes, there is a certain degree of variability between different labs. Correlation analysis showed significant correlation between aneuploidy and CIN for the cell lines in blue (Pearson R = 0.85, P < 0.05) and those in red (Pearson R = 0.80, P < 0.05), but no significant correlation for the data shown in green (R = 0.71, P > 0.05).