Tolerance of Whole-Genome Doubling Propagates Chromosomal Instability and Accelerates Cancer Genome Evolution

Abstract

The contribution of whole-genome doubling to chromosomal instability (CIN) and tumor evolution is unclear. We use long-term culture of isogenic tetraploid cells from a stable diploid colon cancer progenitor to investigate how a genome-doubling event affects genome stability over time. Rare cells that survive genome doubling demonstrate increased tolerance to chromosome aberrations. Tetraploid cells do not exhibit increased frequencies of structural or numerical CIN per chromosome. However, the tolerant phenotype in tetraploid cells, coupled with a doubling of chromosome aberrations per cell, allows chromosome abnormalities to evolve specifi cally in tetraploids, recapitulating chromosomal changes in genomically complex colorectal tumors. Finally, a genome-doubling event is independently predictive of poor relapse-free survival in early-stage disease in two independent cohorts in multivariate analyses [discovery data: hazard ratio (HR), 4.70, 95% confi dence interval (CI), 1.04-21.37; validation data: HR, 1.59, 95% CI, 1.05-2.42]. These data highlight an important role for the tolerance of genome doubling in driving cancer genome evolution. SIGNIFICANCE:Our work sheds light on the importance of whole-genome-doubling events in colorectal cancer evolution. We show that tetraploid cells undergo rapid genomic changes and recapitulate the genetic alterations seen in chromosomally unstable tumors. Furthermore, we demonstrate that a genome-doubling event is prognostic of poor relapse-free survival in this disease type. Cancer Discov; 4(2);

Belinostat and vincristine demonstrate mutually synergistic cytotoxicity associated with mitotic arrest and inhibition of polyploidy in a preclinical model of aggressive diffuse large B cell lymphoma

“…Polyploidy is linked to increased genomic instability and the induction of tumor heterogeneity and ultimately drug resistance. [22][23][24][25] In this study we have determined that the G2/M arrest we previously reported in HDACi-sensitive DLBCL cell lines is due to accumulation of cells in early mitosis, consistent with SAC activation. In contrast, the HDACi belinostat delays mitotic progression but does not prevent mitotic completion in HDACi-resistant DLBCL cell lines.…”

Tetraploidy and CIN: a dangerous combination

“…We recently showed that tetraploid cells are better able to tolerate chromosome missegregation events than diploid cells, resulting in the evolution of CIN in tetraploid cells over extended periods of time in laboratory culture. 3 In this issue of Cell Cycle, Storchova and colleagues confirm these results, and elegantly extend their analysis to search for a mechanistic basis for CIN tolerance in tetraploid cells. 4 In this study, the authors investigate genome stability in tetraploid clones derived from HCT-116 and hTERT-RPE1 cells.…”

“…Given the association between genome duplication and poor patient prognosis. 3,7 together with the tolerance of segregation errors as a major route to CIN, this promises to be a fruitful area for further research.…”

Tetraploidy-associated centrosome overduplication in mouse early embryos

“…The mechanism via which tetraploidization affects genome integrity and other basic biological processes remains poorly understood. A recent study showed that doubling of chromosome number upon tetraploidization increases the chances of chromosome aberrations and cellular tolerance to aneuploidy, potentially promoting expansion of cell population with chromosomal abnormalities [9]. Another possible cause of tetraploidy-linked cellular defects is doubling of centrosome number, which accompanies cell division failure and adversely affects proper mitotic regulation through multipolar spindle formation [10].…”