4.8 Article

Whole-genome doubling confers unique genetic vulnerabilities on tumour cells

Journal

NATURE
Volume 590, Issue 7846, Pages 492-+

Publisher

NATURE RESEARCH
DOI: 10.1038/s41586-020-03133-3

Keywords

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Funding

  1. Canadian Institutes of Health Research Doctoral Foreign Study Award [152266]
  2. National Institutes of Health (NIH) [CA154531, GM117150]
  3. Karin Grunebaum Foundation
  4. Smith Family Awards Program
  5. Melanoma Research Alliance
  6. Searle Scholars Program
  7. American Cancer Society (ACS)
  8. Boston University Clinical and Translational Science Institute Bioinformatics Group
  9. NIH/National Center for Advancing Translational Sciences (NCATS) [1UL1TR001430]

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Whole-genome doubling (WGD) in human cancers results in genetically unstable tetraploid cells that depend on specific signaling pathways and require the KIF18A gene for viability. Targeting vulnerabilities unique to WGD(+) cells presents a potential strategy for cancer therapy.
Whole-genome doubling (WGD) is common in human cancers, occurring early in tumorigenesis and generating genetically unstable tetraploid cells that fuel tumour development(1,2). Cells that undergo WGD (WGD(+) cells) must adapt to accommodate their abnormal tetraploid state; however, the nature of these adaptations, and whether they confer vulnerabilities that can be exploited therapeutically, is unclear. Here, using sequencing data from roughly 10,000 primary human cancer samples and essentiality data from approximately 600 cancer cell lines, we show that WGD gives rise to common genetic traits that are accompanied by unique vulnerabilities. We reveal that WGD(+) cells are more dependent than WGD(-) cells on signalling from the spindle-assembly checkpoint, DNA-replication factors and proteasome function. We also identify KIF18A, which encodes a mitotic kinesin protein, as being specifically required for the viability of WGD(+) cells. Although KIF18A is largely dispensable for accurate chromosome segregation during mitosis in WGD(-) cells, its loss induces notable mitotic errors in WGD(+) cells, ultimately impairing cell viability. Collectively, our results suggest new strategies for specifically targeting WGD(+) cancer cells while sparing the normal, non-transformed WGD(-) cells that comprise human tissue.

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