The impact of monosomies, trisomies and segmental aneuploidies on chromosomal stability

Abstract

Aneuploidy and chromosomal instability are both commonly found in cancer. Chromosomal instability leads to karyotype heterogeneity in tumors and is associated with therapy resistance, metastasis and poor prognosis. It has been hypothesized that aneuploidy per se is sufficient to drive CIN, however due to limited models and heterogenous results, it has remained controversial which aspects of aneuploidy can drive CIN. In this study we systematically tested the impact of different types of aneuploidies on the induction of CIN. We generated a plethora of isogenic aneuploid clones harboring whole chromosome or segmental aneuploidies in human p53-deficient RPE-1 cells. We observed increased segregation errors in cells harboring trisomies that strongly correlated to the number of gained genes. Strikingly, we found that clones harboring only monosomies do not induce a CIN phenotype. Finally, we found that an initial chromosome breakage event and subsequent fusion can instigate breakage-fusion-bridge cycles. By investigating the impact of monosomies, trisomies and segmental aneuploidies on chromosomal instability we further deciphered the complex relationship between aneuploidy and CIN.

HIF1A contributes to the survival of aneuploid and mosaic pre-implantation embryos

“…In our AZ3146-reversine chimeras, AZ3146-treated blastomeres can outcompete reversine-treated blastomeres. These results agree with the well-known relationships between different degrees of aneuploidy/chromosomal instability and cellular fitness 24 .…”

“…Aneuploidy could arises during early cleavage stages 58 and has both immediate effects on cellular fitness and long-term effects on subsequent cell cycles 23,24 . Once generated, and depending on the degree of aneuploidy, an aneuploid blastomere is destined for either death, repair, or survival 59 .…”

Reduction of chromosomal instability and inflammation is a common aspect of adaptation to aneuploidy

“…1A for the working pipeline). As expected, and in line with our previous report (40), all clones initially displayed a growth defect, albeit to different extents. Remarkably, all selected clones exhibited an increase in proliferative capacity over time, indicative of adaptation (Fig.…”

“…Interestingly, upon adaptation we observed a profound decrease in the slope of the correlation between gained genes and CIN levels (0.008766 to 0.002499), suggesting that gained genetic material has a dramatically lower impact on CIN levels in adapted clones as compared to early clones. It was shown before that proteotoxic stress can be a driver of CIN (40). We found that the early aneuploid clones express higher levels of the two key players downstream of PERK activation, namely ATF3 and CHOP/GADD153 (61) (Fig.…”

“…Notably, given the pivotal role of p53 in aneuploidy tolerance, we conducted these experiments using clones harboring a stable shRNA-mediated knockdown of p53 (55). The generation of de novo aneuploid clones was described previously (40). We selected 14 clones with a variety of aneuploidy levels, mostly involving entire chromosomes (Fig S1A).…”