Single-cell genomic variation induced by mutational processes in cancer

• Published in: Nature (London) Vol. 612; no. 7938; pp. 106 - 115
• Main Authors: Funnell, Tyler, O’Flanagan, Ciara H., Williams, Marc J., McPherson, Andrew, McKinney, Steven, Kabeer, Farhia, Lee, Hakwoo, Salehi, Sohrab, Vázquez-García, Ignacio, Shi, Hongyu, Leventhal, Emily, Masud, Tehmina, Eirew, Peter, Yap, Damian, Zhang, Allen W., Lim, Jamie L. P., Wang, Beixi, Brimhall, Jazmine, Biele, Justina, Ting, Jerome, Au, Vinci, Van Vliet, Michael, Liu, Yi Fei, Beatty, Sean, Lai, Daniel, Pham, Jenifer, Grewal, Diljot, Abrams, Douglas, Havasov, Eliyahu, Leung, Samantha, Bojilova, Viktoria, Moore, Richard A., Rusk, Nicole, Uhlitz, Florian, Ceglia, Nicholas, Weiner, Adam C., Zaikova, Elena, Douglas, J. Maxwell, Zamarin, Dmitriy, Weigelt, Britta, Kim, Sarah H., Da Cruz Paula, Arnaud, Reis-Filho, Jorge S., Martin, Spencer D., Li, Yangguang, Xu, Hong, de Algara, Teresa Ruiz, Lee, So Ra, Llanos, Viviana Cerda, Huntsman, David G., McAlpine, Jessica N., Shah, Sohrab P., Aparicio, Samuel
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.12.2022; Nature Publishing Group
• Subjects: 38; 45; 45/23; 45/70; 45/91; 631/208/726/649/2157; 631/67/1517/1709; 631/67/2329; 631/67/69; 64; 692/699/67/1347; BRCA2 protein; Breast cancer; Cellular structure; Cloning; Copy number; Epithelial cells; Epithelium; Evolution; Female; Gene expression; Genetic diversity; Genomes; Genomics; Haplotypes; Homologous recombination; Humanities and Social Sciences; Humans; Inversions; Mammary gland; multidisciplinary; Mutation; Ovarian cancer; Ovarian Neoplasms - genetics; Ovarian Neoplasms - pathology; Phenotypic variations; Phylogeny; Science; Science (multidisciplinary); Single-Cell Analysis; Triple Negative Breast Neoplasms - genetics; Triple Negative Breast Neoplasms - pathology; Tumors
• ISSN: 0028-0836; 1476-4687; 1476-4687
• DOI: 10.1038/s41586-022-05249-0

How cell-to-cell copy number alterations that underpin genomic instability 1 in human cancers drive genomic and phenotypic variation, and consequently the evolution of cancer 2 , remains understudied. Here, by applying scaled single-cell whole-genome sequencing 3 to wild-type, TP53- deficient and TP53 -deficient; BRCA1 -deficient or TP53 -deficient; BRCA2- deficient mammary epithelial cells (13,818 genomes), and to primary triple-negative breast cancer (TNBC) and high-grade serous ovarian cancer (HGSC) cells (22,057 genomes), we identify three distinct ‘foreground’ mutational patterns that are defined by cell-to-cell structural variation. Cell- and clone-specific high-level amplifications, parallel haplotype-specific copy number alterations and copy number segment length variation (serrate structural variations) had measurable phenotypic and evolutionary consequences. In TNBC and HGSC, clone-specific high-level amplifications in known oncogenes were highly prevalent in tumours bearing fold-back inversions, relative to tumours with homologous recombination deficiency, and were associated with increased clone-to-clone phenotypic variation. Parallel haplotype-specific alterations were also commonly observed, leading to phylogenetic evolutionary diversity and clone-specific mono-allelic expression. Serrate variants were increased in tumours with fold-back inversions and were highly correlated with increased genomic diversity of cellular populations. Together, our findings show that cell-to-cell structural variation contributes to the origins of phenotypic and evolutionary diversity in TNBC and HGSC, and provide insight into the genomic and mutational states of individual cancer cells. Single-cell whole-genome sequencing shows that 'foreground' cell-to-cell structural variation and alterations in copy number are associated with genomic diversity and evolution in triple-negative breast and high-grade serous ovarian cancers.