TY - JOUR
T1 - Tolerance of Whole-Genome Doubling Propagates Chromosomal Instability and Accelerates Cancer Genome Evolution
AU - Dewhurst, Sally M.
AU - McGranahan, Nicholas
AU - Burrell, Rebecca A.
AU - Rowan, Andrew J.
AU - Grönroos, Eva
AU - Endesfelder, David
AU - Joshi, Tejal
AU - Mouradov, Dmitri
AU - Gibbs, Peter
AU - Ward, Robyn L.
AU - Hawkins, Nicholas J.
AU - Szallasi, Zoltan Imre
AU - Sieber, Oliver M.
AU - Swanton, Charles
PY - 2014
Y1 - 2014
N2 - 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.
AB - 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.
U2 - 10.1158/2159-8290.CD-13-0285
DO - 10.1158/2159-8290.CD-13-0285
M3 - Journal article
SN - 2159-8274
VL - 4
SP - 175
EP - 185
JO - Cancer Discovery
JF - Cancer Discovery
IS - 2
ER -
