Aurea mediocritas: the importance of a balanced genome

Abstract

Aneuploidy, defined as an abnormal number of chromosomes, is a hallmark of cancer. Paradoxically, aneuploidy generally has a negative impact on cell growth and fitness in nontransformed cells. In this work, we review recent progress in identifying how aneuploidy leads to genomic and chromosomal instability, how cells can adapt to the deleterious effects of aneuploidy, and how aneuploidy contributes to tumorigenesis in different genetic contexts. Finally, we also discuss how aneuploidy might be a target for anticancer therapies.

Figure 1.

Definition of chromosomal instability. (A) In this review, we refer to CIN as an elevated rate of whole-chromosome missegregation. CIN is often operationally defined as lagging, centromere-positive chromosomes at anaphase. Note that this operational definition cannot exclude the loss of the distal ends of chromosomes and thus does not completely exclude structural alterations to the chromosomes. (B) In some studies, CIN has been defined more broadly to include structural chromosome defects. These structural alterations include chromosome bridges or acentric chromosome fragments, which cannot attach to the spindle apparatus and are thus often partitioned into micronuclei. In this review, we adopt the narrow definition of CIN, excluding chromosome bridges and acentric chromosome fragments. (Fluorescence images from Ganem et al. 2009; reprinted, with permission, from the author.)

Figure 2.

Effects of aneuploidy on genomic instability. (A) Aneuploid cells have an elevated rate of DNA mutations and chromosome missegregation compared with diploid cells. (B) A lagging chromosome in anaphase can be damaged if it is located in the proximity of the cleavage furrow. The damaged chromosome(s) can then generate chromosome translocations through nonhomologous end joining (NHEJ). (C) A lagging chromosome can be incorporated into a micronucleus if it does not reach the main chromatin masses. Chromosomes in micronuclei can accumulate damage and undergo fragmentation. The chromosome fragments in the micronucleus can be stitched together, likely through NHEJ, creating a highly rearranged derivative chromosome. In the subsequent mitosis, the nuclear envelope of the micronucleus can break down allowing the rearranged chromosome to be incorporated back into in the main genome.

Figure 3.

Effects of aneuploidy on tumorigenesis. Aneuploidy impairs cellular fitness, potentially preventing tumorigenesis in the absence of tolerating mutations. At the same time, aneuploidy also leads to genomic instability and genetic heterogeneity, which could provide a growth or survival advantage in a specific microenvironment.