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

Abstract:

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.

Authors:

T Funnell, CH O'Flanagan, MJ Williams, A McPherson, S McKinney, F Kabeer, H Lee, S Salehi, I Vázquez-García, H Shi, E Leventhal, T Masud, P Eirew, D Yap, AW Zhang, JLP Lim, B Wang, J Brimhall, J Biele, J Ting, V Au, M Van Vliet, YF Liu, S Beatty, D Lai, J Pham, D Grewal, D Abrams, E Havasov, S Leung, V Bojilova, RA Moore, N Rusk, F Uhlitz, N Ceglia, AC Weiner, E Zaikova, JM Douglas, D Zamarin, B Weigelt, SH Kim, A Da Cruz Paula, JS Reis-Filho, SD Martin, Y Li, H Xu, TR de Algara, SR Lee, VC Llanos, DG Huntsman, JN McAlpine, IMAXT Consortium, SP Shah, S Aparicio

Journal:

Nature

Citation info:

612(7938):106-115

Publication date:

1st Dec 2022

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