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Whole-genome doubling confers unique genetic vulnerabilities on tumour cells

Author

Listed:
  • 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
    Cancer Program, Broad Institute
    Columbia University Medical Center, Member, Herbert Irving Comprehensive Cancer Center)

  • Amity L. Manning

    (Worcester Polytechnic Institute)

  • Joshua D. Campbell

    (Boston University School of Medicine
    Cancer Program, Broad Institute)

  • Neil J. Ganem

    (Boston University School of Medicine
    Boston University School of Medicine)

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.

Suggested Citation

  • 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, 2021. "Whole-genome doubling confers unique genetic vulnerabilities on tumour cells," Nature, Nature, vol. 590(7846), pages 492-497, February.
  • Handle: RePEc:nat:nature:v:590:y:2021:i:7846:d:10.1038_s41586-020-03133-3
    DOI: 10.1038/s41586-020-03133-3
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    Citations

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    Cited by:

    1. Ana Portelinha & Mariana Silva Ferreira & Tatiana Erazo & Man Jiang & Zahra Asgari & Elisa Stanchina & Anas Younes & Hans-Guido Wendel, 2023. "Synthetic lethality of drug-induced polyploidy and BCL-2 inhibition in lymphoma," Nature Communications, Nature, vol. 14(1), pages 1-13, December.
    2. Chunyang Bao & Richard W. Tourdot & Gregory J. Brunette & Chip Stewart & Lili Sun & Hideo Baba & Masayuki Watanabe & Agoston T. Agoston & Kunal Jajoo & Jon M. Davison & Katie S. Nason & Gad Getz & Ken, 2023. "Genomic signatures of past and present chromosomal instability in Barrett’s esophagus and early esophageal adenocarcinoma," Nature Communications, Nature, vol. 14(1), pages 1-22, December.
    3. Revati Darp & Marc A. Vittoria & Neil J. Ganem & Craig J. Ceol, 2022. "Oncogenic BRAF induces whole-genome doubling through suppression of cytokinesis," Nature Communications, Nature, vol. 13(1), pages 1-17, December.
    4. Nikki L. Burdett & Madelynne O. Willis & Ahwan Pandey & Laura Twomey & Sara Alaei & David D. L. Bowtell & Elizabeth L. Christie, 2024. "Timing of whole genome duplication is associated with tumor-specific MHC-II depletion in serous ovarian cancer," Nature Communications, Nature, vol. 15(1), pages 1-13, December.
    5. Marc A. Vittoria & Nathan Kingston & Kristyna Kotynkova & Eric Xia & Rui Hong & Lee Huang & Shayna McDonald & Andrew Tilston-Lunel & Revati Darp & Joshua D. Campbell & Deborah Lang & Xiaowei Xu & Crai, 2022. "Inactivation of the Hippo tumor suppressor pathway promotes melanoma," Nature Communications, Nature, vol. 13(1), pages 1-17, December.

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