TY - JOUR
T1 - Single-cell analysis of somatic mutation burden in mammary epithelial cells of pathogenic BRCA1/2 mutation carriers
AU - Sun, Shixiang
AU - Brazhnik, Kristina
AU - Lee, Moonsook
AU - Maslov, Alexander Y.
AU - Zhang, Yi
AU - Huang, Zhenqiu
AU - Klugman, Susan
AU - Park, Ben H.
AU - Vijg, Jan
AU - Montagna, Cristina
N1 - Publisher Copyright: © 2022 American Society for Clinical Investigation. All rights reserved.
PY - 2022/3/1
Y1 - 2022/3/1
N2 - 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 agematched controls with no genetically increased risk for breast cancer.
AB - 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 agematched controls with no genetically increased risk for breast cancer.
UR - http://www.scopus.com/inward/record.url?scp=85125554401&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85125554401&partnerID=8YFLogxK
U2 - https://doi.org/10.1172/JCI148113
DO - https://doi.org/10.1172/JCI148113
M3 - Article
C2 - 35025760
SN - 0021-9738
VL - 132
JO - Journal of Clinical Investigation
JF - Journal of Clinical Investigation
IS - 5
M1 - e148113
ER -