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Cancer aneuploidies are shaped primarily by effects on tumour fitness

Author

Listed:
  • Juliann Shih

    (Cancer Program, Broad Institute of Harvard and MIT
    Dana-Farber Cancer Institute
    Tufts University School of Medicine
    Kirk Kerkorian School of Medicine at the University of Nevada)

  • Shahab Sarmashghi

    (Cancer Program, Broad Institute of Harvard and MIT
    Dana-Farber Cancer Institute
    Harvard Medical School)

  • Nadja Zhakula-Kostadinova

    (Columbia University Vagelos College of Physicians and Surgeons
    Columbia University Vagelos College of Physicians and Surgeons)

  • Shu Zhang

    (Cancer Program, Broad Institute of Harvard and MIT
    Dana-Farber Cancer Institute)

  • Yohanna Georgis

    (Columbia University Vagelos College of Physicians and Surgeons)

  • Stephanie H. Hoyt

    (Cancer Program, Broad Institute of Harvard and MIT
    Dana-Farber Cancer Institute)

  • Michael S. Cuoco

    (Dana-Farber Cancer Institute)

  • Galen F. Gao

    (Cancer Program, Broad Institute of Harvard and MIT
    Dana-Farber Cancer Institute)

  • Liam F. Spurr

    (Cancer Program, Broad Institute of Harvard and MIT
    Dana-Farber Cancer Institute
    Dana-Farber Cancer Institute)

  • Ashton C. Berger

    (Cancer Program, Broad Institute of Harvard and MIT
    Dana-Farber Cancer Institute)

  • Gavin Ha

    (Cancer Program, Broad Institute of Harvard and MIT
    Dana-Farber Cancer Institute
    Fred Hutchinson Cancer Research Center)

  • Veronica Rendo

    (Cancer Program, Broad Institute of Harvard and MIT
    Dana-Farber Cancer Institute
    Harvard Medical School)

  • Hui Shen

    (Van Andel Institute)

  • Matthew Meyerson

    (Cancer Program, Broad Institute of Harvard and MIT
    Dana-Farber Cancer Institute
    Harvard Medical School)

  • Andrew D. Cherniack

    (Cancer Program, Broad Institute of Harvard and MIT
    Harvard Medical School
    Dana-Farber Cancer Institute)

  • Alison M. Taylor

    (Cancer Program, Broad Institute of Harvard and MIT
    Columbia University Vagelos College of Physicians and Surgeons
    Dana-Farber Cancer Institute)

  • Rameen Beroukhim

    (Cancer Program, Broad Institute of Harvard and MIT
    Dana-Farber Cancer Institute
    Harvard Medical School
    Dana-Farber Cancer Institute)

Abstract

Aneuploidies—whole-chromosome or whole-arm imbalances—are the most prevalent alteration in cancer genomes1,2. However, it is still debated whether their prevalence is due to selection or ease of generation as passenger events1,2. Here we developed a method, BISCUT, that identifies loci subject to fitness advantages or disadvantages by interrogating length distributions of telomere- or centromere-bounded copy-number events. These loci were significantly enriched for known cancer driver genes, including genes not detected through analysis of focal copy-number events, and were often lineage specific. BISCUT identified the helicase-encoding gene WRN as a haploinsufficient tumour-suppressor gene on chromosome 8p, which is supported by several lines of evidence. We also formally quantified the role of selection and mechanical biases in driving aneuploidy, finding that rates of arm-level copy-number alterations are most highly correlated with their effects on cellular fitness1,2. These results provide insight into the driving forces behind aneuploidy and its contribution to tumorigenesis.

Suggested Citation

  • Juliann Shih & Shahab Sarmashghi & Nadja Zhakula-Kostadinova & Shu Zhang & Yohanna Georgis & Stephanie H. Hoyt & Michael S. Cuoco & Galen F. Gao & Liam F. Spurr & Ashton C. Berger & Gavin Ha & Veronic, 2023. "Cancer aneuploidies are shaped primarily by effects on tumour fitness," Nature, Nature, vol. 619(7971), pages 793-800, July.
    • Handle: RePEc:nat:nature:v:619:y:2023:i:7971:d:10.1038_s41586-023-06266-3
    DOI: 10.1038/s41586-023-06266-3
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