title: Tolerance of whole-genome doubling propagates chromosomal instability and accelerates cancer genome evolution.
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.
  
  
  CONCLUSIONS
  Our work sheds light on the importance of whole-genome–doubling events in colorectal cancer evolution. We show that tetraploid cells undergo rapid genomic changes and recapitulate the genetic alterations seen in chromosomally unstable tumors. Furthermore, we demonstrate that a genome-doubling event is prognostic of poor relapse-free survival in this disease type.
authors.affiliation: Cancer Research UK London Research Institute, 44 Lincoln's Inn Fields, London WC2A 3LY, UK.
authors.forename: Sally M
authors.initials: SM
authors.lastname: Dewhurst
authors.affiliation: Cancer Research UK London Research Institute, 44 Lincoln's Inn Fields, London WC2A 3LY, UK.|Centre for Mathematics & Physics in the Life Sciences & Experimental Biology (CoMPLEX), University College London, Physics Building, Gower Street, London WC1E 6BT, UK.
authors.forename: Nicholas
authors.initials: N
authors.lastname: McGranahan
authors.affiliation: Cancer Research UK London Research Institute, 44 Lincoln's Inn Fields, London WC2A 3LY, UK.
authors.forename: Rebecca A
authors.initials: RA
authors.lastname: Burrell
authors.affiliation: Cancer Research UK London Research Institute, 44 Lincoln's Inn Fields, London WC2A 3LY, UK.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Rowan
authors.affiliation: Cancer Research UK London Research Institute, 44 Lincoln's Inn Fields, London WC2A 3LY, UK.
authors.forename: Eva
authors.initials: E
authors.lastname: Grönroos
authors.affiliation: University of Applied Sciences Koblenz, RheinAhrCampus, Department of Mathematics and Technology, Joseph-Rovan-Allee 2, 53424 Remagen, Germany.
authors.forename: David
authors.initials: D
authors.lastname: Endesfelder
authors.affiliation: Technical University of Denmark (DTU), Anker Engelunds Vej 1, 2800 Lyngby, Denmark.
authors.forename: Tejal
authors.initials: T
authors.lastname: Joshi
authors.affiliation: Systems Biology and Personalised Medicine Division, Walter and Eliza Hall Institute, Parkville, VIC, Australia.|Faculty of Medicine, Dentistry and Health Sciences, Department of Surgery, University of Melbourne, Royal Melbourne Hospital, Parkville, VIC, Australia.
authors.forename: Dmitri
authors.initials: D
authors.lastname: Mouradov
authors.affiliation: Systems Biology and Personalised Medicine Division, Walter and Eliza Hall Institute, Parkville, VIC, Australia.|Faculty of Medicine, Dentistry and Health Sciences, Department of Surgery, University of Melbourne, Royal Melbourne Hospital, Parkville, VIC, Australia.|Department of Medical Oncology, Royal Melbourne Hospital, Parkville, VIC, Australia.
authors.forename: Peter
authors.initials: P
authors.lastname: Gibbs
authors.affiliation: Lowy Cancer Research Centre, Prince of Wales Clinical School, University of New South Wales, Sydney, NSW, Australia.
authors.forename: Robyn L
authors.initials: RL
authors.lastname: Ward
authors.affiliation: School of Medical Sciences, University of New South Wales, Sydney, NSW, Australia.
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Hawkins
authors.affiliation: Technical University of Denmark (DTU), Anker Engelunds Vej 1, 2800 Lyngby, Denmark.|Harvard Medical School, 250 Longwood Ave, Boston, MA 02115, United States.
authors.forename: Zoltan
authors.initials: Z
authors.lastname: Szallasi
authors.affiliation: Systems Biology and Personalised Medicine Division, Walter and Eliza Hall Institute, Parkville, VIC, Australia.|Faculty of Medicine, Dentistry and Health Sciences, Department of Surgery, University of Melbourne, Royal Melbourne Hospital, Parkville, VIC, Australia.
authors.forename: Oliver M
authors.initials: OM
authors.lastname: Sieber
authors.affiliation: Cancer Research UK London Research Institute, 44 Lincoln's Inn Fields, London WC2A 3LY, UK.|UCL Cancer Institute, Paul O'Gorman Building, Huntley Street, London WC1E 6BT, UK.
authors.forename: Charles
authors.initials: C
authors.lastname: Swanton
mesh_terms: D045744:Cell Line, Tumor; D043171:Chromosomal Instability; D015179:Colorectal Neoplasms / Q000235:genetics; D056915:DNA Copy Number Variations; D006801:Humans; D009369:Neoplasms / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D010641:Phenotype; D011003:Ploidies; D011123:Polyploidy; D011379:Prognosis