Single-cell analysis of somatic mutation burden in mammary epithelial cells of pathogenic BRCA1/2 mutation carriers

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Abstract

Inherited germline mutations in the BRCA1 (BReast CAncer gene 1) or BRCA2 (BReast CAncer gene 2) 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, non-cancer, mammary epithelial cells of women diagnosed with pathogenic BRCA1 or BRCA2 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 to 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 to those obtained from age-matched controls with no genetically increased risk for breast cancer.

Authors

Shixiang Sun, Kristina Brazhnik, Moonsook Lee, Alexander Y. Maslov, Yi Zhang, Zhenqiu Huang, Susan Klugman, Ben H. Park, Jan Vijg, Cristina Montagna