Cancer aneuploidies are shaped primarily by effects on tumour fitness

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, Veronica Rendo, Hui Shen, Matthew Meyerson, Andrew D. Cherniack, Alison M. Taylor () and Rameen Beroukhim ()
Additional contact information
Juliann Shih: Cancer Program, Broad Institute of Harvard and MIT
Shahab Sarmashghi: Cancer Program, Broad Institute of Harvard and MIT
Nadja Zhakula-Kostadinova: Columbia University Vagelos College of Physicians and Surgeons
Shu Zhang: Cancer Program, Broad Institute of Harvard and MIT
Yohanna Georgis: Columbia University Vagelos College of Physicians and Surgeons
Stephanie H. Hoyt: Cancer Program, Broad Institute of Harvard and MIT
Michael S. Cuoco: Dana-Farber Cancer Institute
Galen F. Gao: Cancer Program, Broad Institute of Harvard and MIT
Liam F. Spurr: Cancer Program, Broad Institute of Harvard and MIT
Ashton C. Berger: Cancer Program, Broad Institute of Harvard and MIT
Gavin Ha: Cancer Program, Broad Institute of Harvard and MIT
Veronica Rendo: Cancer Program, Broad Institute of Harvard and MIT
Hui Shen: Van Andel Institute
Matthew Meyerson: Cancer Program, Broad Institute of Harvard and MIT
Andrew D. Cherniack: Cancer Program, Broad Institute of Harvard and MIT
Alison M. Taylor: Cancer Program, Broad Institute of Harvard and MIT
Rameen Beroukhim: Cancer Program, Broad Institute of Harvard and MIT

Nature, 2023, vol. 619, issue 7971, 793-800

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41586-023-06266-3

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