Single-cell analysis of somatic mutation burden in mammary epithelial cells of pathogenic BRCA1/2 mutation carriers
Shixiang Sun, … , Jan Vijg, Cristina Montagna
Shixiang Sun, … , Jan Vijg, Cristina Montagna
Published January 13, 2022
Citation Information: J Clin Invest. 2022;132(5):e148113. https://doi.org/10.1172/JCI148113.
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Concise Communication Genetics

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

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.

Authors

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

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Figure 2

Mutational spectra in human mammary epithelial cells.

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Mutational spectra in human mammary epithelial cells. (A) Relative contr...
(A) Relative contribution of 6 mutation types to the point mutation spectrum for the indicated mammary sample groups. Data are shown as the mean and 95% confidence intervals of the relative contribution of each mutation type in hTERT-IMEC WT (n = 4) and BRCA1 mutant (n = 4) sample groups and HMEC control sample groups (31 cells from 7 participants), BRCA1/2 mutant carrier sample groups (31 cells from 8 participants), and the outlier cell from the control group. (B) Three mutational signatures (M1, M2, and M3) were de novo identified by nonnegative matrix factorization analysis of the somatic mutations in the different groups in A. “Context” on the x axis represents the mutational profile using the conventional 96 mutation–type classification in COSMIC. This classification is based on the 6 substitution subtypes shown on top, as well as the nucleotides immediately 5′ and 3′ to the mutation (the sorting order is A, C, G and T). The contributions of M1, M2, and M3 signatures to all SNVs in these 5 groups using the nonnegative matrix factorization method is shown on the right.