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Breast Cancer Risk Clues Found By Sequencing Cells From BRCA2 Germline Mutation Carriers

NEW YORK – With the help of single-cell sequencing, a team from Massachusetts General Hospital and elsewhere has identified key alterations that may contribute to breast cancer development in individuals with one risky copy of the BRCA2 gene.

"We present evidence that a failed replication stress response and DNA damage in BRCA2-[heterozygous] tissues result from haploinsufficiency for BRCA2 rather than homozygous loss of function," senior and corresponding author Leif  Ellison, a cancer researcher at the Massachusetts General Hospital and Harvard Medical School, and his colleagues wrote in their study, published online today in Science Advances.

The researchers did single-cell, whole-genome sequencing on cell populations sorted from breast tissue samples from more than two-dozen BRCA2 mutation-positive women who had undergone bilateral prophylactic mastectomies. The participants had just one affected copy of the breast- and ovarian-cancer linked gene, they added, noting that past research has linked such heterozygous BRCA2 mutations to a 50 percent to 80 percent rise in breast cancer risk.

"We sought to unveil the earliest steps in the pathogenesis of BRCA2-associated breast tumors through detailed analysis of histologically normal glands from women harboring germline deleterious mutations who elected to undergo bilateral prophylactic mastectomy," the authors explained.

By comparing genetic profiles in these breast cell populations to those from matched control individuals, the researchers were able to track down alterations that were over-represented in the BRCA2-deficient cells. With this approach, they uncovered sub-chromosomal aneuploidy in more than one-quarter of luminal progenitor cells from BRCA2 mutation carriers, for example. In breast epithelial cells, meanwhile, the heterozygous BRCA2 changes coincided with a jump in DNA damage, along with reduced apoptotic pathway or replication checkpoint activity.

"Genomic analysis of individual cells revealed frequent polyclonal chromosomal damage, which was most prevalent among the subset of epithelial cells that are the suspected cells of origin of these cancers," the authors reported, noting that "[c]orresponding defects in replication stress and DNA damage checkpoint responses in these same cells collectively define a previously unappreciated phenotype for BRCA2 that precedes histological abnormalities in the human breast."

For their analysis, the investigators focused on heterozygous BRCA2 mutation carriers who were breast cancer-free and had no previous exposure to chemotherapy, along with control individuals matched for factors ranging from age to hormone exposure and menopausal status who donated breast tissue samples after elective breast reduction surgeries.

With the help of cell marker-based flow cytometry, the team distinguished between mature luminal, luminal progenitor, and basal epithelial cell populations in the breast tissue samples from participants with or without BRCA2 mutations.

The researchers used single-cell genome sequencing and algorithmic analyses to identify copy number shifts and other somatic alterations in each cell type — identifying patterns supported by RNA sequencing, single-cell PCR, and other follow-up analyses. In samples from 26 women with BRCA2 mutations and 28 without, they also saw an apparent expansion in the proportion of luminal progenitor cells with reduced stress and DNA damage response in samples from aging BRCA2 mutation carriers.

"Although the early genomic changes we observed are likely to include many passenger events, they nevertheless may provide a quantifiable hallmark of the preneoplastic BRCA2 carrier state," the authors wrote. "Tracking the prevalence of DNA-damaged cells in the clinical setting could possibly improve risk prediction for these women, who are faced with the difficult choice of whether to undergo mastectomy long before cancer develops."

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