Single-cell genomic variation induced by mutational processes in cancer.

Tyler Funnell, Ciara H O'Flanagan, Marc J Williams, Andrew McPherson, Steven McKinney, Farhia Kabeer, Hakwoo Lee, Sohrab Salehi, Ignacio Vázquez-García, Hongyu Shi, Emily Leventhal, Tehmina Masud, Peter Eirew, Damian Yap, Allen W Zhang, Jamie L P Lim, Beixi Wang, Jazmine Brimhall, Justina Biele, Jerome Ting, Vinci Au, Michael Van Vliet, Yi Fei Liu, Sean Beatty, Daniel Lai, Jenifer Pham, Diljot Grewal, Douglas Abrams, Eliyahu Havasov, Samantha Leung, Viktoria Bojilova, Richard A Moore, Nicole Rusk, Florian Uhlitz, Nicholas Ceglia, Adam C Weiner, Elena Zaikova, J Maxwell Douglas, Dmitriy Zamarin, Britta Weigelt, Sarah H Kim, Arnaud Da Cruz Paula, Jorge S Reis-Filho, Spencer D Martin, Yangguang Li, Hong Xu, Teresa Ruiz de Algara, So Ra Lee, Viviana Cerda Llanos, David G Huntsman, Jessica N McAlpine, Sohrab P Shah, Samuel Aparicio, Nature 612, 106-115 (2022)


How cell-to-cell copy number alterations that underpin genomic instability1 in human cancers drive genomic and phenotypic variation, and consequently the evolution of cancer2, remains understudied. Here, by applying scaled single-cell whole-genome sequencing3 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.