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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

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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 1

Mutation levels in human mammary epithelial cells.

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Mutation levels in human mammary epithelial cells.
(A) SNV and (B) INDEL...
(A) SNV and (B) INDEL levels in hTERT-IMEC WT (blue) and BRCA1 mutant (red) cells (n = 4 for each type). (C) SNV and (D) INDEL levels in primary HMECs. Graphs on the left in C and D depict the median mutations per sample in both groups (control: blue, n = 7; carrier: red, n = 8; negative binomial generalized linear model), while graphs on the right depict the distributions of single HMECs in control (blue, n = 32) and BRCA1/2 mutant carrier (red, n = 31) groups (negative binomial generalized linear mixed-effect model).

Copyright © 2022 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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