Details

Autor(en) / Beteiligte

• Salehi, Sohrab
• Kabeer, Farhia
• Ceglia, Nicholas
• Andronescu, Mirela
• Williams, Marc J
• Campbell, Kieran R
• Masud, Tehmina
• Wang, Beixi
• Biele, Justina
• Brimhall, Jazmine
• Gee, David
• Lee, Hakwoo
• Ting, Jerome
• Zhang, Allen W
• Tran, Hoa
• O'Flanagan, Ciara
• Dorri, Fatemeh
• Rusk, Nicole
• de Algara, Teresa Ruiz
• Lee, So Ra
• Cheng, Brian Yu Chieh
• Eirew, Peter
• Kono, Takako
• Pham, Jenifer
• Grewal, Diljot
• Lai, Daniel
• Moore, Richard
• Mungall, Andrew J
• Marra, Marco A
• McPherson, Andrew
• Bouchard-Côté, Alexandre
• Aparicio, Samuel
• Shah, Sohrab P

Titel

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

Ist Teil von

• Nature (London), 2021-07, Vol.595 (7868), p.585-590

Ort / Verlag

England: Nature Publishing Group

Erscheinungsjahr

2021

Quelle

MEDLINE

Beschreibungen/Notizen

• 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 models . 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 model 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.