Tetraploidy is permissive for chromosomal instability and accelerates cancer genome evolution


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Sally Dewhurst1, Nicholas McGranahan1, Rebecca Burrell1, Andrew Rowan1, Eva Gronroos1, Charles Swanton1,2
1Cancer Research UK, London Research Institute, London, UK, 2University College London Cancer Institute, Huntley Street, London, UK

Background

An increase in ploidy is one of the hallmarks of many different cancer types, despite polyploid cells being observed rarely in somatic tissues. A complete doubling of the genome, or tetraploidy, has been proposed to be a precursor to aneuploidy (an unbalanced chromosome number) at the onset of carcinogenesis. However tetraploid cells have also been observed at later stages of tumour growth, suggesting polyploidy could also play a role in late emerging tumour phenotypes. We aimed to investigate the effect of polyploidy on long-term genomic stability.

Method

We isolated rare naturally occurring tetraploid cells from the stable diploid colorectal cancer cell line HCT-116. Both diploid and tetraploid clones were grown continuously in culture for over a year, and their genomic instability measured at select time points by methods including clonal FISH, live-cell imaging and SNP6.0 CGH arrays.

Results

Using our isogenic cell line system we observe that tetraploid clones have the ability to tolerate and propagate both numerical and structural chromosome aberrations, whereas the diploid clones remain stable over time. Strikingly all the tetraploid clones show convergent loss of chromosome 4q by later passage numbers. We show that this chromosome region is also lost in highly unstable colorectal tumours, meaning that our system is recapitulating losses seen in vivo.

Conclusion

In a stable diploid cell line, we show that a tetraploidisation event can lead to tolerance of chromosomal instability. We are now investigating how tetraploidy may have conferred this tolerance. Furthermore we see that tetraploidy can accelerate cancer genome evolution, as all tetraploid clones show convergent loss of a chromosome region that is associated with genome instability in vivo. We are interested in whether this chromosome region has a function in the toleration and propagation of chromosomal instability.