Clonal fitness inferred from time-series modelling of single-cell cancer genomes

Nature. 2021 Jul;595(7868):585-590. doi: 10.1038/s41586-021-03648-3. Epub 2021 Jun 23.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line, Tumor
  • Cisplatin / pharmacology
  • Clone Cells / pathology
  • DNA Copy Number Variations*
  • Drug Resistance, Neoplasm*
  • Female
  • Genetic Fitness
  • Humans
  • Mice
  • Models, Statistical
  • Neoplasm Transplantation
  • Triple Negative Breast Neoplasms / genetics*
  • Tumor Suppressor Protein p53 / genetics
  • Whole Genome Sequencing


  • TP53 protein, human
  • Tumor Suppressor Protein p53
  • Cisplatin