Whole-Genome Duplication and Genome Instability in Cancer Cells: Double the Trouble

Whole-genome duplication (WGD) is one of the most common genomic abnormalities in cancers. WGD can provide a source of redundant genes to buffer the deleterious effect of somatic alterations and facilitate clonal evolution in cancer cells. The extra DNA and centrosome burden after WGD is associated with an elevation of genome instability. Causes of genome instability are multifaceted and occur throughout the cell cycle. Among these are DNA damage caused by the abortive mitosis that initially triggers tetraploidization, replication stress and DNA damage associated with an enlarged genome, and chromosomal instability during the subsequent mitosis in the presence of extra centrosomes and altered spindle morphology. Here, we chronicle the events after WGD, from tetraploidization instigated by abortive mitosis including mitotic slippage and cytokinesis failure to the replication of the tetraploid genome, and finally, to the mitosis in the presence of supernumerary centrosomes. A recurring theme is the ability of some cancer cells to overcome the obstacles in place for preventing WGD. The underlying mechanisms range from the attenuation of the p53-dependent G(1) checkpoint to enabling pseudobipolar spindle formation via the clustering of supernumerary centrosomes. These survival tactics and the resulting genome instability confer a subset of polyploid cancer cells proliferative advantage over their diploid counterparts and the development of therapeutic resistance.

Automated summary

Whole-genome duplication (WGD) is a common genomic abnormality in cancers that provides redundant genes and facilitates clonal evolution in cancer cells. After WGD, the increased DNA and centrosome burden lead to genome instability, caused by factors such as DNA damage, replication stress, and altered spindle morphology. Cancer cells can overcome these obstacles through mechanisms like attenuating the p53-dependent G(1) checkpoint and forming pseudobipolar spindles with supernumerary centrosomes. These survival tactics and resulting genome instability confer proliferative advantage and therapeutic resistance to polyploid cancer cells.