Single-cell genomic variation induced by mutational processes in cancer
Tyler Funnell, Ciara H. O’Flanagan, Marc Williams, Andrew McPherson, Steven McKinney, Farhia Kabeer, Hakwoo Lee, Sohrab Salehi, Ignacio Vázquez-Garćıa, Hongyu Shi, Emily Leventhal, Tehmina Masud, Peter Eirew, Damian Yap, Allen W. Zhang, Jamie Lim, Beixi Wang, Jazmine Brimhall, Justina Biele, Jerome Ting, Vinci Au, Michael Van Vliet, Yifei Liu, Sean Beatty, Daniel Lai, Jenifer Pham, Diljot Grewal, Douglas N. 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, Hongxia Xu, Teresa Ruiz de Algara, So Ra Lee, Viviana Cerda Llanos, David G. Huntsman, Jessica N. McAlpine, Gregory J. Hannon, Georgia Battistoni, Dario Bressan, Ian G. Cannell, Hannah Casbolt, Cristina Jauset, Tatjana Kovačević, Claire M. Mulvey, Fiona Nugent, Marta Ribes, Isabella Pearson, Fatime Qosaj, Kirsty Sawicka, Sophia A. Wild, Elena Williams, Emma Laks, Austin Smith, Daniel Lai, Andrew Roth, Shankar Balasubramanian, Maximilian Lee, Bernd Bodenmiller, Marcel Burger, Laura Kuett, Sandra Tietscher, Jonas Windhager, Edward S. Boyden, Shahar Alon, Yi Cui, Amauche Emenari, Daniel Goodwin, Emmanouil D. Karagiannis, Anubhav Sinha, Asmamaw T. Wassie, Carlos Caldas, Alejandra Bruna, Maurizio Callari, Wendy Greenwood, Giulia Lerda, Yaniv Eyal-Lubling, Oscar M. Rueda, Abigail Shea, Owen Harris, Robby Becker, Flaminia Grimaldo, Suvi Harris, Sara Lisa Vogl, Johanna A. Joyce, Spencer S. Watson
Abstract
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.