The clonal and mutational evolution spectrum of primary triple-negative breast cancers
Open accessAbstract
Primary triple-negative breast cancers (TNBCs), a tumour type defined by lack of oestrogen receptor, progesterone receptor and ERBB2 gene amplification, represent approximately 16% of all breast cancers. Here we show in 104 TNBC cases that at the time of diagnosis these cancers exhibit a wide and continuous spectrum of genomic evolution, with some having only a handful of coding somatic aberrations in a few pathways, whereas others contain hundreds of coding somatic mutations. High-throughput RNA sequencing (RNA-seq) revealed that only approximately 36% of mutations are expressed. Using deep re-sequencing measurements of allelic abundance for 2,414 somatic mutations, we determine for the first time-to our knowledge-in an epithelial tumour subtype, the relative abundance of clonal frequencies among cases representative of the population. We show that TNBCs vary widely in their clonal frequencies at the time of diagnosis, with the basal subtype of TNBC showing more variation than non-basal TNBC. Although p53 (also known as TP53), PIK3CA and PTEN somatic mutations seem to be clonally dominant compared to other genes, in some tumours their clonal frequencies are incompatible with founder status. Mutations in cytoskeletal, cell shape and motility proteins occurred at lower clonal frequencies, suggesting that they occurred later during tumour progression. Taken together, our results show that understanding the biology and therapeutic responses of patients with TNBC will require the determination of individual tumour clonal genotypes.
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p53 is mutated in approximately 50% of all cancers.
“It is estimated that p53 is mutated in approximately 50% of all cancers with 60% of TNBCs bearing mutations in p53 (14, 15);”
From Potentiation of carboplatin-mediated DNA damage by the Mdm2 modulator Nutlin-3a in a humanized orthotopic breast-to-lung metastatic model (2015) · cites this paper as [15]
60% of triple-negative breast cancers bear mutations in p53.
“It is estimated that p53 is mutated in approximately 50% of all cancers with 60% of TNBCs bearing mutations in p53 (14, 15);”
From Potentiation of carboplatin-mediated DNA damage by the Mdm2 modulator Nutlin-3a in a humanized orthotopic breast-to-lung metastatic model (2015) · cites this paper as [15]
About 60% of basal TNBCs carry p53 mutations, and roughly 90% of p53 mutations fall in the DNA binding domain.
“Approximately 60% of basal TNBCs bear mutations in p53 (15) and ~90% of mutations in p53 occur in the DNA binding domain.”
From Potentiation of carboplatin-mediated DNA damage by the Mdm2 modulator Nutlin-3a in a humanized orthotopic breast-to-lung metastatic model (2015) · cites this paper as [15]
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- Authors
- Shah, S. P., Roth, A., Goya, R., Oloumi, A., Ha, G., Zhao, Y., Turashvili, G., Ding, J., Tse, K., Haffari, G., Bashashati, A., Prentice, L. M., Khattra, J., Burleigh, A., Yap, D., Bernard, V., McPherson, A., Shumansky, K., Crisan, A., Giuliany, R., Heravi-Moussavi, A., Rosner, J., Lai, D., Birol, I., Varhol, R., Tam, A., Dhalla, N., Zeng, T., Ma, K., Chan, S. K., Griffith, M., Moradian, A., Cheng, S.-W. G., Morin, G. B., Watson, P., Gelmon, K., Chia, S., Chin, S.-F., Curtis, C., Rueda, O. M., Pharoah, P. D., Damaraju, S., Mackey, J., Hoon, K., Harkins, T., Tadigotla, V., Sigaroudinia, M., Gascard, P., Tlsty, T., Costello, J. F., Meyer, I. M., Eaves, C. J., Wasserman, W. W., Jones, S., Huntsman, D., Hirst, M., Caldas, C., Marra, M. A., & Aparicio, S.
- Affiliations
- University of British Columbia (CA)
- Canada's Michael Smith Genome Sciences Centre (CA)
- BC Cancer Agency (CA)
- University of Cambridge (GB)
- University of Southern California (US)
- Cancer Research UK (GB)
- University of Alberta (CA)
- University of California, San Francisco (US)
- Corresponding author
- Shah, Sohrab P.
- Caldas, Carlos
- Marra, Marco A.
- Aparicio, Samuel
- ORCID
- Shah, Sohrab P.
- Roth, Andrew
- Ha, Gavin
- Zhao, Yongjun
- Turashvili, Gulisa
- Ding, Jiarui
- Haffari, Gholamreza
- Bashashati, Ali
- Prentice, Leah M.
- Burleigh, Angela
- Yap, Damian
- McPherson, Andrew
- Crisan, Anamaria
- Rosner, Jamie
- Lai, Daniel
- Varhol, Richard
- Tam, Angela
- Griffith, Malachi
- Moradian, Annie
- Cheng, S.-W. Grace
- Morin, Gregg B.
- Watson, Peter
- Gelmon, Karen
- Chia, Stephen
- Chin, Suet-Feung
- Curtis, Christina
- Rueda, Oscar M.
- Pharoah, Paul D.
- Damaraju, Sambasivarao
- Mackey, John
- Harkins, Timothy
- Gascard, Philippe
- Tlsty, Thea
- Costello, Joseph F.
- Meyer, Irmtraud M.
- Eaves, Connie J.
- Wasserman, Wyeth W.
- Jones, Steven
- Huntsman, David
- Hirst, Martin
- Caldas, Carlos
- Marra, Marco A.
- Aparicio, Samuel
- Venue
- Nature
- Published
- 2012-04-04
- Volume
- 486
- Issue
- 7403
- Pages
- 395-399
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC3863681
- OpenAlex
- W2063382533
- Cited by
- 1,967
- References
- 23
- Citations by year
- 2026: 40 · 2025: 61 · 2024: 71 · 2023: 131 · 2022: 132 · 2021: 119 · 2020: 131 · 2019: 120 · 2018: 135 · 2017: 173 · 2016: 179 · 2015: 198 · 2014: 199 · 2013: 201 · 2012: 76
- FWCI
- 71.57
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- MDC Repository (Max-Delbrueck-Center for Molecular Medicine) (submittedVersion)
- eSpace (Curtin University) (submittedVersion)
- Funders
- U.S. Department of Defense
- Memorial Sloan-Kettering Cancer Center
- Canada's Michael Smith Genome Sciences Centre
- Canadian Breast Cancer Research Alliance
- Michael Smith Health Research BC
- Cancer Research UK
- National Institute for Health and Care Research (NF-SI-0611-10154)
- Cure Brain Cancer Foundation
- BC Cancer Foundation
- National Institutes of Health
- Imperial Experimental Cancer Medicine Centre
- BC Cancer Agency
- National Institute of General Medical Sciences (R01GM084875)
- National Institute of Environmental Health Sciences (U01ES017154)
- Congressionally Directed Medical Research Programs
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer Genomics and Diagnostics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Breast Cancer Treatment Studies
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › BRCA gene mutations in cancer
- Keywords
- triple-negative breast cancer, clonal evolution, somatic mutations, copy number variation, cancer genomics, TP53 mutation, PIK3CA mutation, PTEN mutation, basal subtype, tumor progression, founder mutation, clonal heterogeneity
- MeSH terms
- Alleles, Breast Neoplasms, Clone Cells, DNA Mutational Analysis, Female, Genotype, Humans, Mutation, Reproducibility of Results, Gene Expression Regulation, Neoplastic, Point Mutation, Sequence Analysis, RNA, Disease Progression, Evolution, Molecular, Gene Expression Profiling, INDEL Mutation, DNA Copy Number Variations, Precision Medicine, High-Throughput Nucleotide Sequencing
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