Aneuploidy: instigator and inhibitor of tumorigenesis

Abstract

Aneuploidy, an aberrant chromosome number, has been recognized as a common characteristic of cancer cells for more than 100 years and has been suggested as a cause of tumorigenesis for nearly as long. However, this proposal had remained untested due to the difficulty of selectively generating aneuploidy without causing other damage. Using Cenp-E heterozygous animals, which develop whole chromosome aneuploidy in the absence of other defects, we have found that aneuploidy promotes tumorigenesis in some contexts and inhibits it in others. These findings confirm that aneuploidy can act oncogenically and reveal a previously unsuspected role for aneuploidy as a tumor suppressor.

Figure 1. Aneuploidy can drive or inhibit tumors, similar to DNA damage

Wild type cells do not exhibit genetic instability and maintain a diploid genome with intact growth regulatory pathways, consistent with continued cell survival. Moderate levels of genetic instability caused by mutations in mismatch repair genes or by missegregation of 1-3 chromosomes per division (due, for instance, to Cenp-E heterozygosity in the absence of other defects), promote cell growth and tumorigenesis. High levels of genetic instability, caused by chemotherapeutic agents such as cisplatin or missegregation of large numbers of chromosomes (10-15) per division, result in cell death and tumor suppression.