التفاصيل البيبلوغرافية
| العنوان: |
Clonal fitness inferred from time-series modelling of single-cell cancer genomes |
| المؤلفون: |
Sohrab Salehi, Farhia Kabeer, Nicholas Ceglia, Mirela Andronescu, Marc J. Williams, Kieran R. Campbell, Tehmina Masud, Beixi Wang, Justina Biele, Jazmine Brimhall, David Gee, Hakwoo Lee, J |
| المصدر: |
Nature, Nature. 595(7868):585-590 |
| سنة النشر: |
2021 |
| الوصف: |
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. |
| نوع الوثيقة: |
redif-article |
| اللغة: |
English |
| DOI: |
10.1038/s41586-021-03648 |
| الإتاحة: |
https://ideas.repec.org/a/nat/nature/v595y2021i7868d10.1038_s41586-021-03648-3.html |
| رقم الأكسشن: |
edsrep.a.nat.nature.v595y2021i7868d10.1038.s41586.021.03648.3 |
| قاعدة البيانات: |
RePEc |
