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Ongoing chromosomal instability and karyotype evolution in human colorectal cancer organoids

Bolhaqueiro, A. C. F., Ponsioen, B., Bakker, B., Klaasen, S. J., Kucukkose, E., van Jaarsveld, R. H., Vivié, J., Verlaan-Klink, I., Hami, N., Spierings, D. C. J., Sasaki, N., Dutta, D., Boj, S. F., Vries, R. G. J., Lansdorp, P. M., van de Wetering, M., van Oudenaarden, A., Clevers, H., Kranenburg, O., Foijer, F., Snippert, H. J. G. & Kops, G. J. P. L., May-2019, In : Nature Genetics. 51, 5, p. 824-834 16 p.

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  • Ongoing chromosomal instability and karyotype evolution in human colorectal cancer organoids

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DOI

  • Ana C F Bolhaqueiro
  • Bas Ponsioen
  • Bjorn Bakker
  • Sjoerd J Klaasen
  • Emre Kucukkose
  • Richard H van Jaarsveld
  • Judith Vivié
  • Ingrid Verlaan-Klink
  • Nizar Hami
  • Diana C J Spierings
  • Nobuo Sasaki
  • Devanjali Dutta
  • Sylvia F Boj
  • Robert G J Vries
  • Peter M Lansdorp
  • Marc van de Wetering
  • Alexander van Oudenaarden
  • Hans Clevers
  • Onno Kranenburg
  • Floris Foijer
  • Hugo J G Snippert
  • Geert J P L Kops

Chromosome segregation errors cause aneuploidy and genomic heterogeneity, which are hallmarks of cancer in humans. A persistent high frequency of these errors (chromosomal instability (CIN)) is predicted to profoundly impact tumor evolution and therapy response. It is unknown, however, how prevalent CIN is in human tumors. Using three-dimensional live-cell imaging of patient-derived tumor organoids (tumor PDOs), we show that CIN is widespread in colorectal carcinomas regardless of background genetic alterations, including microsatellite instability. Cell-fate tracking showed that, although mitotic errors are frequently followed by cell death, some tumor PDOs are largely insensitive to mitotic errors. Single-cell karyotype sequencing confirmed heterogeneity of copy number alterations in tumor PDOs and showed that monoclonal lines evolved novel karyo-types over time in vitro. We conclude that ongoing CIN is common in colorectal cancer organoids, and propose that CIN levels and the tolerance for mitotic errors shape aneuploidy landscapes and karyotype heterogeneity.

Original languageEnglish
Pages (from-to)824-834
Number of pages16
JournalNature Genetics
Volume51
Issue number5
Publication statusPublished - May-2019

    Keywords

  • TUMOR EVOLUTION, DNA-DAMAGE, INTRATUMOR HETEROGENEITY, GENETIC INSTABILITY, SEGREGATION ERRORS, MIS-SEGREGATION, HUMAN COLON, IN-VITRO, ANEUPLOIDY, CELLS

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