Monosomies, trisomies and segmental aneuploidies differentially affect 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 in segmental aneuploidies. This suggests that monosomies, trisomies and segmental aneuploidies have fundamentally different effects on chromosomal instability and these results help us to decipher the complex relationship between aneuploidy and CIN.

Proliferative advantage of specific aneuploid cells drives evolution of tumor karyotypes

“…For euploid cells, we use the proliferation rate value β ( K 2 n ) = l n 2 d −1 , based on division time for the earliest thymocyte, double negative, stages (DN1-DN4) (Petrie and Zúñiga-Pflücker, 2007). For aneuploid cells, the proliferation rate is β ( K ≠ K .2 n ) = 0.8 l n 2 d −1 , because aneuploid cells proliferate roughly 20% slower in comparison to diploid cells (Hintzen et al, 2021; Williams et al, 2008). Given that in this mouse model (Trakala et al, 2021) all cells have the same probability of missegregating their chromosomes independent of their karyotype, we use the same missegregation rates values for all karyotypes, including both euploid and aneuploid cells.…”

“…One of key processes which drives karyotype evolution is chromosome missegregation, which is increased for many tumor karyotypes and termed chromosome instability (CIN) (Hintzen et al, 2021; Nicholson & Cimini, 2013; Thompson & Compton, 2008). Missegregation includes gain or loss of one or a few chromosomes due to incorrect attachment of chromosomes to the mitotic spindle (Bakhoum et al, 2009; Cimini, 2008; Dewhurst et al, 2014; Nicholson et al, 2015; Thompson & Compton, 2011b).…”

“…Another key process for karyotype evolution is cell proliferation, which determines how the total number of cells with a certain karyotype changes over time. In particular, it was measured that aneuploid cells typically proliferate slower than euploid cells (Hintzen et al, 2021; Williams et al, 2008). However, certain aneuploid karyotypes with a favorable combination of chromosome gains or losses can lead to enhanced cell proliferation (Ben-David et al, 2014; Heyde et al, 2021; Rohban & Campaner, 2015).…”

The Dynamic Instability of the Aneuploid Genome

“…It has to be noted that the vast majority of studies conducted so far have employed an heterogenous population of aneuploid cells, comprising both chromosome gains and losses as well as cycling and arrested cells. In the future, it will be important to explore more in details the contributions of specific trisomies vs. monosomies, an effort that has been recently pioneered by the Medema and Storchova labs ( Chunduri et al, 2021 ; Hintzen et al, 2021 ). Further, it remains unclear what are the exact mechanisms by which the aneuploid status is associated with increasing genome instability.…”

Polar Chromosomes—Challenges of a Risky Path

“…In addition, complex molecular signaling mechanisms that operate during congression, error correction, and implications of those on the formation and correction of different erroneous attachments await more comprehensive studies. An important part of such studies would be long-term tracking of chromosome fates during whole mitosis in different systems, including nontransformed and tumor cells, which would lead toward achieving the goal of discriminating the cellular consequences of individual whole chromosome aneuploidies from different sources [227]. Finally, it will be important to establish whether defects in chromosome alignment and the underlying molecular mechanisms are directly responsible for human diseases such as cancer and whether targeting chromosome congression represents an effective therapeutic approach.…”