Single-cell genomic variation induced by mutational processes in cancer
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. ,   IMAXT Consortium, Hannon Gregory J. , Battistoni Georgia , Bressan Dario , Cannell Ian G. , Casbolt Hannah , Jauset Cristina , Kovačević Tatjana , Mulvey Claire M. , Nugent Fiona , Ribes Marta Paez , Pearson Isabella , Qosaj Fatime , Sawicka Kirsty , Wild Sophia A. , Williams Elena , Laks Emma , Smith Austin , Lai Daniel , Roth Andrew , Balasubramanian Shankar , Lee Maximilian , Bodenmiller Bernd , Burger Marcel , Kuett Laura , Tietscher Sandra , Windhager Jonas , Boyden Edward S. , Alon Shahar , Cui Yi , Emenari Amauche , Goodwin Daniel R. , Karagiannis Emmanouil D. , Sinha Anubhav , Wassie Asmamaw T. , Caldas Carlos , Bruna Alejandra , Callari Maurizio , Greenwood Wendy , Lerda Giulia , Eyal-Lubling Yaniv , Rueda Oscar M. , Shea Abigail , Harris Owen , Becker Robby , Grimaldo Flaminia , Harris Suvi , Vogl Sara Lisa , Joyce Johanna A. , Watson Spencer S. , Tavare Simon , Dinh Khanh N. , Fisher Eyal , Kunes Russell , Walton Nicholas A. , Al Sa’d Mohammed , Chornay Nick , Dariush Ali , González-Solares Eduardo A. , González-Fernández Carlos , Yoldaş Aybüke Küpcü , Miller Neil , Zhuang Xiaowei , Fan Jean , Lee Hsuan , Sepúlveda Leonardo A. , Xia Chenglong , Zheng Pu , Shah Sohrab P. , Aparicio Samuel 
Published: October 2022

AbstractHow cell-to-cell copy number alterations that underpin genomic instability1in human cancers drive genomic and phenotypic variation, and consequently the evolution of cancer2, remains understudied. Here, by applying scaled single-cell whole-genome sequencing3to wild-type,TP53-deficient andTP53-deficient;BRCA1-deficient orTP53-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.