Prophylactic mastectomy is currently the only breast cancer prevention strategy for women with inherited BRCA1 or BRCA2 mutations. While often effective, this strategy significantly impacts quality of life and does not prevent the development of cancers arising in other tissues (e.g., pancreatic and prostate cancers). Thus, better interception strategies are urgently needed. Given this, characterization of the earliest genetic alterations in breast tissues from individuals at high-risk of developing breast cancer could lay the groundwork for the discovery of new prevention measures. In an international study, collaborators Sam Aparicio (University of British Columbia), Joan Brugge (Harvard Medical School), and Sohrab Shah (Memorial Sloan Kettering Cancer Center) performed scaled single-cell whole genome sequencing (scWGS) (DLP+) of non-cancer containing breast tissues from high-risk BRCA1/BRCA2 germline mutation carrier and BRCA-wildtype women to investigate the landscape of chromosomal copy number alterations (CNAs), potentially identifying the earliest genetic alterations that may play a critical role in cancer development.
In this study, the authors (including co-first authors Marc Williams (MSKCC), Michael Oliphant (HMS) and Vinci Au (UBC)) showed that while the presence of CNAs was a relatively rare event in breast epithelial cells, small populations of cells with one or two of a specific subset of CNAs (e.g. 1q gain and 16q, 22q, 7q, and 10q loss) were detectable in almost all breast tissues. Interestingly, CNAs were found exclusively in the luminal cells that line the lobules and ducts—pathways through which milk flows in the breast—and were absent in the surrounding contractile cells that support and enclose the luminal layer, further supporting previous studies that implicate luminal cells as the cell of origin for most breast cancers. Notably, in tissues from BRCA1 or BRCA2 mutation carriers, these CNAs occur prior to the loss of heterozygosity (LOH) of the wildtype allele, indicating that LOH may not contribute to this process.
Previous studies have shown that the recurrent CNAs detected in this study are among the most common alterations associated with ductal carcinoma in situ (DCIS) and malignant breast tumors, suggesting that they may represent the earliest genetic alterations that prime cells for cancer development following additional mutational events, and thus play a potential pivotal role in the early development of the disease. For BRCA1 and BRCA2 mutation carriers, these alterations could increase the ability of cells to survive the loss of the normal copy of BRCA1/2 which causes genomic instability, and progress toward malignant cancer. These insights could potentially lead to the development of more effective strategies for prevention and intervention.