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.

Authors:

S Salehi, F Kabeer, N Ceglia, M Andronescu, MJ Williams, KR Campbell, T Masud, B Wang, J Biele, J Brimhall, D Gee, H Lee, J Ting, AW Zhang, H Tran, C O'Flanagan, F Dorri, N Rusk, TR de Algara, SR Lee, BYC Cheng, P Eirew, T Kono, J Pham, D Grewal, D Lai, R Moore, AJ Mungall, MA Marra, IMAXT Consortium, A McPherson, A Bouchard-Côté, S Aparicio, SP Shah

Journal:

Nature

Citation info:

595(7868):585-590

Publication date:

1st Jul 2021

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