CNAs and Breast Cancer Initiation

Cancer-associated mutations have been documented in normal tissues, but the prevalence and nature of somatic copy number alterations and their role in tumor initiation and evolution is not well understood. My initial project in the Brugge Lab utilized single-cell DNA sequencing to describe the landscape of copy number alterations (CNAs) in breast epithelial cells from women with normal or high risk of developing breast cancer. Accumulation of individual cells with one or two of a specific subset of CNAs (e.g. 1q gain, 16q and 10q loss) is detectable in both normal and high-risk breast tissues and, in those from BRCA1 or BRCA2 mutations carriers. These CNAs, which are among the most common associated with ductal carcinoma in situ (DCIS) and malignant breast tumors, are enriched almost exclusively in luminal cells not basal myoepithelial cells. Allele-specific analysis of the enriched CNAs reveals that each allele is independently altered, demonstrating convergent evolution of these CNAs in an individual breast. Our findings demonstrate that chromosomal alterations in normal breast epithelium partially mirror those of established cancer genomes and are chromosome- and cell lineage-specific.

Future work will involve using the Sleeping Beauty 16q loss mouse model in collaboration with Sean Egan, as well as patient-derived normal breast organoids, to determine the functional role of CNAs in breast cancer development. Importantly, the expertise I developed in patient breast tissue processing and organoid culture were pivotal in creating innovative models of ER+ breast cancer. These models, as well as my developing expertise in analysis/interpretation of genetic alterations will be essential for my independent research program.