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

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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Publication Details

Journal
Nature Genetics
Published
2024-11-20
DOI
https://doi.org/10.1038/s41588-024-01988-0
Citations
22
Primary Topic
BRCA gene mutations in cancer
Type
article
Field-Weighted Citation Impact
12.11
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article

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

Walter L. Goh, Cathy Liu, Shailesh Agarwal, Caroline Baril et al.
22 citations
Nature Genetics
BRCA gene mutations in cancer
12.11
article

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

Walter L. Goh, Cathy Liu, Shailesh Agarwal, Caroline Baril, Vinci Au, Adam C. Weiner, Ciara H. O’Flanagan, Michael Oliphant, Sohrab P. Shah, Vikas Prabhakar, Joan S. Brugge, Daniel Lai, Andrew McPherson, McKenna Moore, Lauren O’Connor, Deborah Dillon, Samuel Aparício, Sean Beatty, Michael Van Vliet, K. Barbara Norton, Marc Williams, Alicia Pollaci, Judy E. Garber, Jacky CH Yiu, Diljot Grewal
article en
22 citations

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.

Nature GeneticsVol. 56(12)
Brigham and Women's Hospital (US), BC Cancer Agency (CA), Memorial Sloan Kettering Cancer Center (US), Harvard University (US), University of British Columbia (CA), Dana-Farber Cancer Institute (US)
Openalex Percentile: Top 1%
BRCA gene mutations in cancer
12.11
DOIOpen Access PDFOpenAlex
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