Whole-genome doubling in tissues and tumors

Abstract

The overwhelming majority of proliferating somatic human cells are diploid, and this genomic state is typically maintained across successive cell divisions. However, failures in cell division can induce a whole-genome doubling (WGD) event, in which diploid cells transition to a tetraploid state. While some WGDs are developmentally programmed to produce nonproliferative tetraploid cells with specific cellular functions, unscheduled WGDs can be catastrophic: erroneously arising tetraploid cells are ill-equipped to cope with their doubled cellular and chromosomal content and quickly become genomically unstable and tumorigenic. Deciphering the genetics that underlie the genesis, physiology, and evolution of whole-genome doubled (WGD⁺) cells may therefore reveal therapeutic avenues to selectively eliminate pathological WGD⁺ cells.

Keywords: CIN; KIF18A; binucleate; polyploid; tetraploid; whole-genome doubling.

Figure 1:. WGD in physiologic and oncogenic development.

Programmed WGD occurs through multiple mechanisms in normal developmental physiology. Some examples include: cell fusion in osteoclasts, cytokinesis failure in hepatocytes, endomitosis in megakaryocytes, and endoreduplication in trophoblasts. Tumor cells undergo WGD via similar mechanisms during their evolution as a result of errors, such as: viral-induced cell fusion, cytokinesis failure, mitotic slippage, and endoreduplication.

Figure 2:. WGD requires cellular adaptations.

Cells which experience unscheduled WGD duplicate their cellular contents (e.g., centrosomes) as well as their genome. The doubling of these structures imposes unique stresses which WGD⁺ cells must overcome to proliferate. Clear evidence of this is seen with extra centrosomes. If WGD⁺ cells do not cluster surplus centrosomes during mitosis, the result is a multipolar division with uneven distribution of chromosomes and the production of non-viable daughter cells. To successfully proliferate, WGD⁺ cells must adapt to cluster their extra centrosomes in order to form a pseudo-bipolar spindle and produce viable progeny.

Figure 3:. Replication stress in WGD cells.

Following cell division, DNA replication factors scale up in G1 in preparation for entry into S phase. In diploid cells, this results in sufficient numbers of factors required for successful DNA replication; however, in WGD cells there is insufficient scaling of factors to meet the demand for DNA replication, leading to the firing of fewer replication forks, increased replication stress, and genomic instability.

Figure 4:. WGD alters 3D chromosome spatial orientation and gene expression.

The spatial orientation of chromosomes within the nucleus has a direct impact on gene expression. Segments of DNA that fall within “A compartments” are highly expressed while segments of DNA that fall within “B compartments” are not. WGD results in changes in nuclear size and chromosomal numbers which alters the 3D spatial chromosomal orientation within the nucleus driving changes in gene expression by altering which DNA segments are positioned in A and B compartments.