1 Department of Systems Biology, Technical University of Denmark2 Center for Biological Sequence Analysis, Department of Systems Biology, Technical University of Denmark3 Cancer Systems Biology, Center for Biological Sequence Analysis, Department of Systems Biology, Technical University of Denmark4 Cancer Research UK, London Research Institute5 Koblenz University of Applied Sciences6 Walter and Eliza Hall Institute of Medical Research7 Prince of Wales Clinical School8 University of New South Wales9 Department of Bio and Health Informatics, Technical University of Denmark10 Walter and Eliza Hall Institute of Medical Research
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 specifically 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% confidence 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.
Cancer Discovery, 2014, Vol 4, Issue 2, p. 175-185