Cited by 34Cancer Genomics and DiagnosticsBRCA gene mutations in cancerGenomic variations and chromosomal abnormalities

Luminal breast epithelial cells of BRCA1 or BRCA2 mutation carriers and noncarriers harbor common breast cancer copy number alterations

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Williams, Marc J., Oliphant, Michael U. J., Au, Vinci, Liu, Cathy, Baril, Caroline, O’Flanagan, Ciara, Lai, Daniel, Beatty, Sean +17 more·2024·Nature Genetics

Abstract

The prevalence and nature of somatic copy number alterations (CNAs) in breast epithelium and their role in tumor initiation and evolution remain poorly understood. Using single-cell DNA sequencing (49,238 cells) of epithelium from BRCA1 and BRCA2 carriers or wild-type individuals, we identified recurrent CNAs (for example, 1q-gain and 7q, 10q, 16q and 22q-loss) that are present in a rare population of cells across almost all samples (n = 28). In BRCA1/BRCA2 carriers, these occur before loss of heterozygosity (LOH) of wild-type alleles. These CNAs, common in malignant tumors, are enriched in luminal cells but absent in basal myoepithelial cells. Allele-specific analysis of prevalent CNAs reveals that they arose by independent mutational events, consistent with convergent evolution. BRCA1/BRCA2 carriers contained a small percentage of cells with extreme aneuploidy, featuring loss of TP53, BRCA1/BRCA2 LOH and multiple breast cancer-associated CNAs. Our findings suggest that CNAs arising in normal luminal breast epithelium are precursors to clonally expanded tumor genomes.

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  • A group of already transformed tumors can remain stable and controlled for years before progressing into symptomatic disease.

    “This evidence reinforces the idea that a group of already transformed tumors can remain stable and controlled for years before progressing into symptomatic disease.21,100,101”

    From Evolution of Multiple Myeloma from a Genomic Perspective (2026) · cites this paper as [100]

    The Results identify rare cancer-like cells, and the Discussion suggests they may come from microscopic premalignant lesions. Neither section establishes that already transformed tumors remain stable and controlled for years before becoming symptomatic; searches for long-term stability and progression found no such passage. Page numbers were unavailable in our copy. (LLM, conf=0.76)

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  1. [10]PCAWG Transcriptome Core Group et al. Genomic basis for RNA alterations in cancer. Nature578, 129–136 (2020). PMC7054216 32025019
  2. [59]Davis, A., Gao, R. & Navin, N. Tumor evolution: linear, branching, neutral or punctuated? Biochim. Biophys. Acta 1867, 151–161 (2017). PMC5558210 28110020

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Authors
Williams, M. J., Oliphant, M. U. J., Au, V., Liu, C., Baril, C., O’Flanagan, C., Lai, D., Beatty, S., Van Vliet, M., Yiu, J. C., O’Connor, L., Goh, W. L., Pollaci, A., Weiner, A. C., Grewal, D., McPherson, A., Norton, K., Moore, M., Prabhakar, V., Agarwal, S., Garber, J. E., Dillon, D. A., Shah, S. P., Brugge, J. S., & Aparicio, S.
Affiliations
  • Memorial Sloan Kettering Cancer Center (US)
  • Harvard University (US)
  • University of British Columbia (CA)
  • Dana-Farber Cancer Institute (US)
  • Brigham and Women's Hospital (US)
Corresponding author
  • Shah, Sohrab P.
  • Brugge, Joan S.
  • Aparicio, Samuel
Venue
Nature Genetics
Published
2024-11-20
Volume
56
Issue
12
Pages
2753-2762
ISSN
  • 1061-4036 (ISSN-L)
  • 1546-1718
OpenAlex
W4404566931
Cited by
34
References
68
Citations by year
2026: 16 · 2025: 17 · 2024: 1
FWCI
6.82
Type
journal article
Language
en
Open access
Locations
  • Nature Genetics (publishedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
Funders
  • National Human Genome Research Institute (RM1HG011014)
  • National Cancer Institute (K99CA256508, P50CA247749, P30CA008748, R35CA242428, P50CA168504)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer Genomics and Diagnostics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › BRCA gene mutations in cancer
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomic variations and chromosomal abnormalities
Keywords
somatic copy number alterations, BRCA1 mutation carriers, BRCA2 mutation carriers, breast cancer, loss of heterozygosity, aneuploidy, p53 deficiency, convergent evolution, tumor initiation, clonal evolution, single-cell DNA sequencing
MeSH terms
Breast, Breast Neoplasms, Epithelial Cells, Female, Heterozygote, Humans, Mutation, BRCA1 Protein, Loss of Heterozygosity, BRCA2 Protein, DNA Copy Number Variations, Single-Cell Analysis

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