Whole-genome doubling confers unique genetic vulnerabilities on tumour cells

Ryan J. Quinton, Amanda DiDomizio, Marc A. Vittoria, Kristýna Kotýnková, Carlos J. Ticas, Sheena Patel, Yusuke Koga, Jasmine Vakhshoorzadeh, Nicole Hermance, Taruho S. Kuroda, Neha Parulekar, Alison M. Taylor, Amity L. Manning, Joshua D. Campbell and Neil J. Ganem ()
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Ryan J. Quinton: Boston University School of Medicine
Amanda DiDomizio: Boston University School of Medicine
Marc A. Vittoria: Boston University School of Medicine
Kristýna Kotýnková: Boston University School of Medicine
Carlos J. Ticas: Boston University School of Medicine
Sheena Patel: Boston University School of Medicine
Yusuke Koga: Boston University School of Medicine
Jasmine Vakhshoorzadeh: Boston University School of Medicine
Nicole Hermance: Worcester Polytechnic Institute
Taruho S. Kuroda: Mie University Graduate School of Medicine
Neha Parulekar: Boston University School of Medicine
Alison M. Taylor: Dana-Farber Cancer Institute
Amity L. Manning: Worcester Polytechnic Institute
Joshua D. Campbell: Boston University School of Medicine
Neil J. Ganem: Boston University School of Medicine

Nature, 2021, vol. 590, issue 7846, 492-497

Abstract: Abstract Whole-genome doubling (WGD) is common in human cancers, occurring early in tumorigenesis and generating genetically unstable tetraploid cells that fuel tumour development1,2. 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.

Date: 2021
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DOI: 10.1038/s41586-020-03133-3

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