Clonal fitness inferred from time-series modelling of single-cell cancer genomes Journal Article
| Authors: | Salehi, S.; Kabeer, F.; Ceglia, N.; Andronescu, M.; Williams, M. J.; Campbell, K. R.; Masud, T.; Wang, B.; Biele, J.; Brimhall, J.; Gee, D.; Lee, H.; Ting, J.; Zhang, A. W.; Tran, H.; O’Flanagan, C.; Dorri, F.; Rusk, N.; de Algara, T. R.; Lee, S. R.; Cheng, B. Y. C.; Eirew, P.; Kono, T.; Pham, J.; Grewal, D.; Lai, D.; Moore, R.; Mungall, A. J.; Marra, M. A.; IMAXT Consortium; McPherson, A.; Bouchard-Côté, A.; Aparicio, S.; Shah, S. P. |
| Contributor: | Vazquez-Garcia, I. |
| Article Title: | Clonal fitness inferred from time-series modelling of single-cell cancer genomes |
| Abstract: | Progress in defining genomic fitness landscapes in cancer, especially those defined by copy number alterations (CNAs), has been impeded by lack of time-series single-cell sampling of polyclonal populations and temporal statistical models1–7. Here we generated 42,000 genomes from multi-year time-series single-cell whole-genome sequencing of breast epithelium and primary triple-negative breast cancer (TNBC) patient-derived xenografts (PDXs), revealing the nature of CNA-defined clonal fitness dynamics induced by TP53 mutation and cisplatin chemotherapy. Using a new Wright–Fisher population genetics model8,9 to infer clonal fitness, we found that TP53 mutation alters the fitness landscape, reproducibly distributing fitness over a larger number of clones associated with distinct CNAs. Furthermore, in TNBC PDX models with mutated TP53, inferred fitness coefficients from CNA-based genotypes accurately forecast experimentally enforced clonal competition dynamics. Drug treatment in three long-term serially passaged TNBC PDXs resulted in cisplatin-resistant clones emerging from low-fitness phylogenetic lineages in the untreated setting. Conversely, high-fitness clones from treatment-naive controls were eradicated, signalling an inversion of the fitness landscape. Finally, upon release of drug, selection pressure dynamics were reversed, indicating a fitness cost of treatment resistance. Together, our findings define clonal fitness linked to both CNA and therapeutic resistance in polyclonal tumours. © 2021, The Author(s), under exclusive licence to Springer Nature Limited. |
| Keywords: | genotype; phylogenetics; genome; disease treatment; experimental study; cell component; cancer; induced response; martes |
| Journal Title: | Nature |
| Volume: | 595 |
| Issue: | 7868 |
| ISSN: | 0028-0836 |
| Publisher: | Nature Publishing Group |
| Date Published: | 2021-07-22 |
| Start Page: | 585 |
| End Page: | 590 |
| Language: | English |
| PMCID: | PMC8396073 |
| DOI: | 10.1038/s41586-021-03648-3 |
| PROVIDER: | scopus |
| PUBMED: | 34163070 |
| DOI/URL: | |
| Notes: | Article -- Source: Scopus |
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