Abstract
Inherited germline mutations in the breast cancer gene 1 (BRCA1) or BRCA2 genes (herein BRCA1/2) greatly increase the risk of breast and ovarian cancer, presumably by elevating somatic mutational errors as a consequence of deficient DNA repair. However, this has never been directly demonstrated by a comprehensive analysis of the somatic mutational landscape of primary, noncancer, mammary epithelial cells of women diagnosed with pathogenic BRCA1/2 germline mutations. Here, we used an accurate, single-cell whole-genome sequencing approach to first show that telomerized primary mammary epithelial cells heterozygous for a highly penetrant BRCA1 variant displayed a robustly elevated mutation frequency as compared with their isogenic control cells. We then demonstrated a small but statistically significant increase in mutation frequency in mammary epithelial cells isolated from the breast of BRCA1/2 mutation carriers as compared with those obtained from age-matched controls with no genetically increased risk for breast cancer.
Highlights
Breast cancer is the most common cancer in women worldwide [1]
To establish in vivo relevance of these results, we isolated non-tumor mammary epithelial cells from women diagnosed with a BRCA1/2 germline mutation (8 subjects for a total of 31 cells; Supplementary Figure 1, Supplementary Table 1) as well as from age-matched control women undergoing reduction mammoplasty purely for cosmetic reasons (7 subjects for a total of 33 cells)
From each subject 2-8 single primary human mammary epithelial cells (HMECs) were sequenced alongside genomic DNA obtained from bulk mammary gland tissue of the same individuals to correct for germline variants
Summary
Breast cancer is the most common cancer in women worldwide [1]. Up to 10% of breast cancer is due to genetic predisposition [2], with inherited mutations in BRCA1 or BRCA2 (BRCA1/2) accounting for most cases. We calculated the median SNV frequency of all cells for each subject and compared the BRCA1/2 mutant and control groups. These results indicate a more modest effect of heritable pathogenic BRCA1/2 germline mutations on somatic mutations in primary cells in vivo compared to established isogenic hTERT-
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