Luminal breast epithelial cells of BRCA1 or BRCA2 mutation carriers and noncarriers harbor common breast cancer copy number alterations Journal Article
| 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. H.; 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. |
| Article Title: | Luminal breast epithelial cells of BRCA1 or BRCA2 mutation carriers and noncarriers harbor common breast cancer copy number alterations |
| 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. © The Author(s) 2024. |
| Keywords: | adult; controlled study; human tissue; gene mutation; major clinical study; genetics; mutation; microscopy; metabolism; breast cancer; breast; genotype; pathology; breast neoplasms; brca1 protein; brca2 protein; heterozygote; wild type; protein p53; protein mdmx; breast tumor; telomerase reverse transcriptase; epithelium cell; epithelial cells; x chromosome; myoepithelium cell; heterozygosity loss; loss of heterozygosity; chromosome loss; aneuploidy; brca1 protein, human; chromosome 6; chromosome 1q; chromosome 16q; chromosome 7q; chromosome 10q; chromosome 17p; chromosome 22q; dna copy number variations; copy number variation; cell dna; single cell analysis; single-cell analysis; chromosome 16; chromosome arm; brca2 protein, human; invasive breast cancer; humans; human; female; article; whole genome sequencing; convergent evolution; breast epithelium cell |
| Journal Title: | Nature Genetics |
| Volume: | 56 |
| Issue: | 12 |
| ISSN: | 1061-4036 |
| Publisher: | Nature Publishing Group |
| Date Published: | 2024-12-01 |
| Start Page: | 2753 |
| End Page: | 2762 |
| Language: | English |
| DOI: | 10.1038/s41588-024-01988-0 |
| PUBMED: | 39567747 |
| PROVIDER: | scopus |
| PMCID: | PMC11631757 |
| DOI/URL: | |
| Notes: | Source: Scopus |
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