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The life history of 21 breast cancers |
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| Authors: | Nik-Zainal Serena Van Loo Peter Wedge David C Alexandrov Ludmil B Greenman Christopher D Lau King Wai Raine Keiran Jones David Marshall John Ramakrishna Manasa Shlien Adam Cooke Susanna L Hinton Jonathan Menzies Andrew Stebbings Lucy A Leroy Catherine Jia Mingming Rance Richard Mudie Laura J Gamble Stephen J Stephens Philip J McLaren Stuart Tarpey Patrick S Papaemmanuil Elli Davies Helen R Varela Ignacio McBride David J Bignell Graham R Leung Kenric Butler Adam P Teague Jon W Martin Sancha Jönsson Goran Mariani Odette Boyault Sandrine Miron Penelope Fatima Aquila Langerød Anita |
| Institution: | 1 Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton CB10 1SA, UK 2 Center for the Biology of Disease, VIB, Herestraat 49 Box 602, B-3000 Leuven, Belgium 3 Department of Human Genetics, KU Leuven, Herestraat 49 Box 602, B-3000 Leuven, Belgium 4 Department of Computing, University of East Anglia, Norwich NR4 7TJ, UK 5 The Genome Analysis Centre, Norwich Research Park, Norwich NR4 7UH, UK 6 Breakthrough Breast Cancer Research Unit, Kings College, London SE1 9RT, UK 7 Institut Curie, Department of Tumor Biology, 26 rue d'Ulm, 75248 Paris Cedex 05, France 8 Universite Lyon 1, INCa-Synergie, Centre Leon Berard, 28 rue Laennec, Lyon Cedex 08, France 9 Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, MA 02215, USA 10 Department of Genetics, Institute for Cancer Research, Oslo University Hospital, The Norwegian Radium Hospital, O310 Oslo, Norway 11 Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia V6T 2B5, Canada 12 Molecular Oncology, British Columbia Cancer Research Centre, Vancouver, British Columbia V5Z 1L3, Canada 13 Erasmus Medical Centre, Postbus 2040, 3000 CA Rotterdam, The Netherlands 14 Department of Oncology, Lund University, BMC C13, SE-221 84 Lund, Sweden 15 Brigham and Women's Hospital, Harvard Medical School, 75 Francis St, Boston, MA 02115, USA 16 K. G. Jebsen Center for Breast Cancer Research, Institute for Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo N-0310, Norway 17 Department of Haematology, Addenbrooke's Hospital, Cambridge CB2 0QQ, UK 18 Department of Haematology, University of Cambridge, Cambridge CB2 2XY, UK |
| Abstract: | 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. |
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