Journal Article

Whole-genome doubling confers unique genetic vulnerabilities on tumour cells

Ganem, Neil J., Kuroda, Taruho S., Quinton, Ryan J., Patel, Sheena, Vakhshoorzadeh, Jasmine, Manning, Amity L., Campbell, Joshua D., Hermance, Nicole, Kotýnková, Kristýna, DiDomizio, Amanda, Vittoria, Marc A., Ticas, Carlos J., Koga, Yusuke, Parulekar, Neha, Taylor, Alison M.

2021

Overview

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. Cancer cells that have undergone whole-genome doubling are more reliant than their near-diploid counterparts on DNA-replication factors, the spindle-assembly checkpoint and a mitotic kinesin protein, KIF18A.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 13 / 13/1 / 13/106 / 13/109 / 13/44 / 13/89 / 14 / 14/19 / 14/63 / 38 / 631/67/68 / 631/80/641/1655 / Abnormal Karyotype - drug effects / Adaptation / Breast Neoplasms - genetics / Breast Neoplasms - pathology / Cancer / Cancer cells / Cell division / Cell Line, Tumor / Cell viability / Chromosomes / Deoxyribonucleic acid / DNA / DNA biosynthesis / Female / Gene expression / Genes, Lethal - genetics / Genetic aspects / Genome, Human - genetics / Genomes / Human tissues / Humanities and Social Sciences / Humans / Kinases / Kinesin / Kinesin - deficiency / Kinesin - genetics / Kinesin - metabolism / M Phase Cell Cycle Checkpoints - drug effects / Male / Mitosis / Mitosis - drug effects / Mitosis - genetics / multidisciplinary / Mutation / Neoplasms - genetics / Neoplasms - pathology / Proteasome Endopeptidase Complex - metabolism / Proteasomes / Reproducibility of Results / Science / Science (multidisciplinary) / Spindle Apparatus - drug effects / Tetraploidy / Tumor cell lines / Tumorigenesis / Tumors