Cancer aneuploidies are shaped primarily by effects on tumour fitness

• Published in: Nature (London) Vol. 619; no. 7971; pp. 793 - 800
• Main Authors: Shih, Juliann, Sarmashghi, Shahab, Zhakula-Kostadinova, Nadja, Zhang, Shu, Georgis, Yohanna, Hoyt, Stephanie H., Cuoco, Michael S., Gao, Galen F., Spurr, Liam F., Berger, Ashton C., Ha, Gavin, Rendo, Veronica, Shen, Hui, Meyerson, Matthew, Cherniack, Andrew D., Taylor, Alison M., Beroukhim, Rameen
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 27.07.2023; Nature Publishing Group
• Subjects: 45; 631/114/2785; 631/181/2474; 631/208/1405; 631/67/69; 631/67/70; Aneuploidy; Cancer; Cell Lineage; Cell Transformation, Neoplastic - genetics; Centromere - genetics; Chromosome 8; Chromosomes; Chromosomes, Human, Pair 8 - genetics; DNA Copy Number Variations - genetics; DNA helicase; Fitness; Gene loci; Genes; Genes, Tumor Suppressor; Genomes; Humanities and Social Sciences; Humans; Information sources; Loci; multidisciplinary; Mutation; Neoplasms - genetics; Neoplasms - pathology; Oncogenes - genetics; Science; Science (multidisciplinary); Telomere - genetics; Telomeres; Tumorigenesis; Tumors; Yeast
• ISSN: 0028-0836; 1476-4687; 1476-4687
• DOI: 10.1038/s41586-023-06266-3

Aneuploidies—whole-chromosome or whole-arm imbalances—are the most prevalent alteration in cancer genomes 1 , 2 . However, it is still debated whether their prevalence is due to selection or ease of generation as passenger events 1 , 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 fitness 1 , 2 . These results provide insight into the driving forces behind aneuploidy and its contribution to tumorigenesis. A study reports the development of an algorithm, BISCUT, that detects genomic loci under selective pressure by relying on the distribution of breakpoints across chromosome arms, and uses it to explore how aneuploidies affect tumorigenesis.