The life history of 21 breast cancers.

Serena Nik-Zainal, Peter Van Loo, David C Wedge, Ludmil B Alexandrov, Christopher D Greenman, King Wai Lau, Keiran Raine, David Jones, John Marshall, Manasa Ramakrishna, Adam Shlien, Susanna L Cooke, Jonathan Hinton, Andrew Menzies, Lucy A Stebbings, Catherine Leroy, Mingming Jia, Richard Rance, Laura J Mudie, Stephen J Gamble, Philip J Stephens, Stuart McLaren, Patrick S Tarpey, Elli Papaemmanuil, Helen R Davies, Ignacio Varela, David J McBride, Graham R Bignell, Kenric Leung, Adam P Butler, Jon W Teague, Sancha Martin, Goran Jönsson, Odette Mariani, Sandrine Boyault, Penelope Miron, Aquila Fatima, Anita Langerød, Samuel A J R Aparicio, Andrew Tutt, Anieta M Sieuwerts, Åke Borg, Gilles Thomas, Anne Vincent Salomon, Andrea L Richardson, Anne-Lise Børresen-Dale, P Andrew Futreal, Michael R Stratton, Peter J Campbell,, Cell 149, 994-1007 (2012)
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Cancer evolves dynamically as clonal expansions supersede one another driven by shifting selective pressures, mutational processes, and disrupted cancer genes. These processes mark the genome, such that a cancer’s life history is encrypted in the somatic mutations present. We developed algorithms to decipher this narrative and applied them to 21 breast cancers. Mutational processes evolve across a cancer’s lifespan, with many emerging late but contributing extensive genetic variation. Subclonal diversification is prominent, and most mutations are found in just a fraction of tumor cells. Every tumor has a dominant subclonal lineage, representing more than 50% of tumor cells. Minimal expansion of these subclones occurs until many hundreds to thousands of mutations have accumulated, implying the existence of long-lived, quiescent cell lineages capable of substantial proliferation upon acquisition of enabling genomic changes. Expansion of the dominant subclone to an appreciable mass may therefore represent the final rate-limiting step in a breast cancer’s development, triggering diagnosis.