Single-cell genomic variation induced by mutational processes in cancer
- PMID: 36289342
- PMCID: PMC9712114
- DOI: 10.1038/s41586-022-05249-0
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.
© 2022. The Author(s).
Conflict of interest statement
B.W. reports ad hoc membership of the advisory board of Repare Therapeutics, outside the scope of this study. J.S.R.-F. reports receiving personal or consultancy fees from Goldman Sachs, REPARE Therapeutics, Paige.AI and Eli Lilly, membership of the scientific advisory boards of VolitionRx, REPARE Therapeutics and Paige.AI, membership of the Board of Directors of Grupo Oncoclinicas and ad hoc membership of the scientific advisory boards of Roche Tissue Diagnostics, Ventana Medical Systems, Novartis, Genentech and InVicro, outside the scope of this study. D.G.H is the Chief Medical officer of Imagia Canexia Health, outside the scope of this study. S.P.S. and S.A. are shareholders and consultants of Canexia Health and shareholders of Imagia Canexia Health, outside the scope of this study The remaining authors declare no competing interests.
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