Tolerance of Whole-Genome Doubling Propagates Chromosomal Instability and Accelerates Cancer Genome Evolution

Sally M. Dewhurst, Nicholas McGranahan, Rebecca A. Burrell, Andrew J. Rowan, Eva Grönroos, David Endesfelder, Tejal Joshi, Dmitri Mouradov, Peter Gibbs, Robyn L. Ward, Nicholas J. Hawkins, Zoltan Imre Szallasi, Oliver M. Sieber, Charles Swanton

    Research output: Contribution to journalJournal articleResearchpeer-review

    Abstract

    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.
    Original languageEnglish
    JournalCancer Discovery
    Volume4
    Issue number2
    Pages (from-to)175-185
    ISSN2159-8274
    DOIs
    Publication statusPublished - 2014

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