Breast tumours maintain a reservoir of subclonal diversity during expansion
Open accessAbstract
Our knowledge of copy number evolution during the expansion of primary breast tumours is limited 1,2. Here, to investigate this process, we developed a single-cell, single-molecule DNA-sequencing method and performed copy number analysis of 16,178 single cells from 8 human triple-negative breast cancers and 4 cell lines. The results show that breast tumours and cell lines comprise a large milieu of subclones (7-22) that are organized into a few (3-5) major superclones. Evolutionary analysis suggests that after clonal TP53 mutations, multiple loss-of-heterozygosity events and genome doubling, there was a period of transient genomic instability followed by ongoing copy number evolution during the primary tumour expansion. By subcloning single daughter cells in culture, we show that tumour cells rediversify their genomes and do not retain isogenic properties. These data show that triple-negative breast cancers continue to evolve chromosome aberrations and maintain a reservoir of subclonal diversity during primary tumour growth.
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Our data are comparable to the recent findings of Navin, Michor and colleagues, who identified between seven to 22 subclones on scCNV analysis of triple negative breast cancer tumors and cell lines.
“Our data are comparable to the recent findings of Navin, Michor and colleagues, who identified between seven to 22 subclones on scCNV analysis of triple negative breast cancer tumors and cell lines (Minussi 2021)53.”
From Occult polyclonality of preclinical pancreatic cancer models drives in vitro evolution (2022) · cites this paper as [53]
Cancer cells retain a "reservoir" of subclonal diversity, such that isolated single cell clones re-diversify their genomes within a relatively short time frame, at a calculated pace of one CNV event every four cell divisions.
“Notably, these investigators also reported that cancer cells retain a “reservoir” of subclonal diversity, such that isolated single cell clones re-diversify their genomes within a relatively short time frame, at a calculated pace of one CNV event every four cell divisions.”
From Occult polyclonality of preclinical pancreatic cancer models drives in vitro evolution (2022) · cites this paper as [53]
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References 70 · Cited by 256
Research works printed but not linked: 2
- [17]Gao R Punctuated copy number evolution and clonal stasis in triple-negative breast cancer. Nat Genet, doi: 10.1038/ng.3641 (2016). PMC5042845 27526321 · DOI
- [64]H, W. ggplot2: Elegant Graphics for Data Analysis. Springer-Verlag New York., < https://ggplot2.tidyverse.org. > (2016).
- Authors
- Minussi, D. C., Nicholson, M. D., Ye, H., Davis, A., Wang, K., Baker, T., Tarabichi, M., Sei, E., Du, H., Rabbani, M., Peng, C., Hu, M., Bai, S., Lin, Y.-W., Schalck, A., Multani, A., Ma, J., McDonald, T. O., Casasent, A., Barrera, A., Chen, H., Lim, B., Arun, B., Meric-Bernstam, F., Van Loo, P., Michor, F., & Navin, N. E.
- Affiliations
- The University of Texas MD Anderson Cancer Center (US)
- Harvard University (US)
- The Francis Crick Institute (GB)
- Corresponding author
- Navin, Nicholas E.
- ORCID
- Minussi, Darlan C.
- Nicholson, Michael D.
- Ye, Hanghui
- Davis, Alexander
- Wang, Kaile
- Baker, Toby
- Tarabichi, Maxime
- Sei, Emi
- Du, Haowei
- Rabbani, Mashiat
- Peng, Cheng
- Hu, Min
- Bai, Shanshan
- Schalck, Aislyn
- Multani, Asha
- Ma, Jin
- McDonald, Thomas O.
- Chen, Hui
- Lim, Bora
- Arun, Banu
- Van Loo, Peter
- Michor, Franziska
- Navin, Nicholas E.
- Venue
- Nature
- Published
- 2021-03-24
- Volume
- 592
- Issue
- 7853
- Pages
- 302-308
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC8049101
- OpenAlex
- W3137654632
- Cited by
- 256
- References
- 70
- Citations by year
- 2026: 32 · 2025: 41 · 2024: 55 · 2023: 45 · 2022: 56 · 2021: 27
- FWCI
- 18.36
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Digital Access to Scholarship at Harvard (DASH) (Harvard University) (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- Wellcome Trust (FC001202)
- Francis Crick Institute (10202)
- National Cancer Institute (R01CA240526, U54CA143798, R01CA236864, P30CA016672)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer Genomics and Diagnostics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Single-cell and spatial transcriptomics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomic variations and chromosomal abnormalities
- Keywords
- triple-negative breast cancer, copy number evolution, tumor evolution, TP53 mutation, loss of heterozygosity, genome doubling, genomic instability, chromosomal abnormalities, single-cell genomics, tumor heterogeneity
- MeSH terms
- Single Molecule Imaging, Base Sequence, Breast Neoplasms, Chromosome Aberrations, Clone Cells, DNA Mutational Analysis, Humans, Models, Genetic, Cell Lineage, Evolution, Molecular, Loss of Heterozygosity, Genomic Instability, Cell Line, Tumor, Cell Proliferation, DNA Copy Number Variations, Single-Cell Analysis, Mutation Rate, Triple Negative Breast Neoplasms
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