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The Life History of 21 Breast Cancers
Open accessAbstract
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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“Cancer whole genome sequencing (WGS) is now feasible, with thousands of matched tumor-normal pairs successfully sequenced to date, revealing novel biological insights2–4.”
From Whole-genome sequencing of triple-negative breast cancers in a population-based clinical study (2019) · cites this paper as [3]
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Metadata
- Authors
- Nik-Zainal, S., Van Loo, P., Wedge, D. C., Alexandrov, L. B., Greenman, C. D., Lau, K. W., Raine, K., Jones, D., Marshall, J., Ramakrishna, M., Shlien, A., Cooke, S. L., Hinton, J., Menzies, A., Stebbings, L. A., Leroy, C., Jia, M., Rance, R., Mudie, L. J., Gamble, S. J., Stephens, P. J., McLaren, S., Tarpey, P. S., Papaemmanuil, E., Davies, H. R., Varela, I., McBride, D. J., Bignell, G. R., Leung, K., Butler, A. P., Teague, J. W., Martin, S., Jönsson, G., Mariani, O., Boyault, S., Miron, P., Fatima, A., Langerød, A., Aparicio, S. A. J. R., Tutt, A., Sieuwerts, A. M., Borg, Å., Thomas, G., Salomon, A. V., Richardson, A. L., Børresen-Dale, A.-L., Futreal, P. A., Stratton, M. R., & Campbell, P. J.
- Affiliations
- Wellcome Sanger Institute (GB)
- University of East Anglia (GB)
- King's College London (GB)
- Institut Curie (FR)
- Lyon 1 Université (FR)
- Dana-Farber Cancer Institute (US)
- Oslo University Hospital (NO)
- University of British Columbia (CA)
- Erasmus MC (NL)
- Lund University (SE)
- Brigham and Women's Hospital (US)
- University of Cambridge (GB)
- Corresponding author
- Campbell, Peter J.
- ORCID
- Wedge, David C.
- Alexandrov, Ludmil B.
- Lau, King Wai
- Raine, Keiran
- Jones, David
- Marshall, John
- Ramakrishna, Manasa
- Shlien, Adam
- Hinton, Jonathan
- Menzies, Andrew
- Jia, Mingming
- Tarpey, Patrick S.
- Papaemmanuil, Elli
- Davies, Helen R.
- Varela, Ignacio
- McBride, David J.
- Teague, Jon W.
- Martin, Sancha
- Jönsson, Goran
- Mariani, Odette
- Boyault, Sandrine
- Miron, Penelope
- Aparicio, Samuel A.J.R.
- Tutt, Andrew
- Sieuwerts, Anieta M.
- Borg, Åke
- Thomas, Gilles
- Richardson, Andrea L.
- Futreal, P. Andrew
- Stratton, Michael R.
- Campbell, Peter J.
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2012-05
- Volume
- 149
- Issue
- 5
- Pages
- 994-1007
- ISSN
- 0092-8674 (ISSN-L)
- PMC
- PMC3428864
- OpenAlex
- W2109991075
- Cited by
- 1,443
- References
- 39
- Citations by year
- 2026: 51 · 2025: 77 · 2024: 83 · 2023: 84 · 2022: 71 · 2021: 112 · 2020: 105 · 2019: 93 · 2018: 114 · 2017: 103 · 2016: 100 · 2015: 126 · 2014: 139 · 2013: 140 · 2012: 44
- FWCI
- 47.68
- Type
- journal article
- Language
- en
- Update notices
- erratum (2015-08-13)
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Cell (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- ENLIGHTEN (Jurnal Bimbingan dan Konseling Islam) (acceptedVersion)
- UEA Digital Repository (University of East Anglia) (acceptedVersion)
- Research Portal (King's College London) (submittedVersion, other-oa)
- Lirias (KU Leuven) (submittedVersion)
- Lund University Publications (Lund University) (submittedVersion)
- Research Explorer (The University of Manchester) (submittedVersion)
- Apollo (University of Cambridge) (submittedVersion, cc-by)
- Apollo (cc-by)
- Funders
- Wellcome Trust (088340, 093867, WT088340MA, 098051)
- National Institute for Health and Care Research
- European Commission (242006)
- National Cancer Institute (CA 089393, P50CA089393)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer Genomics and Diagnostics
- Health Sciences › Medicine › Oncology › Cancer Cells and Metastasis
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Single-cell and spatial transcriptomics
- Keywords
- breast cancer, tumor evolution, clonal evolution, somatic mutations, mutational processes, clonal expansion, cancer genomics
- MeSH terms
- Algorithms, Breast Neoplasms, Cell Transformation, Neoplastic, Chromosome Aberrations, Female, Humans, Mutation, Point Mutation, Clonal Evolution
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