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

Autor: Sun S; Department of Genetics, Albert Einstein College of Medicine, New York, New York, USA., Brazhnik K; Department of Genetics, Albert Einstein College of Medicine, New York, New York, USA., Lee M; Department of Genetics, Albert Einstein College of Medicine, New York, New York, USA., Maslov AY; Department of Genetics, Albert Einstein College of Medicine, New York, New York, USA.; Laboratory of Applied Genomic Technologies, Voronezh State University of Engineering Technologies, Voronezh, Russia., Zhang Y; Department of Genetics, Albert Einstein College of Medicine, New York, New York, USA.; Department of Radiation Oncology, Rutgers Cancer Institute of New Jersey, New Brunswick, New Jersey, USA., Huang Z; Department of Genetics, Albert Einstein College of Medicine, New York, New York, USA., Klugman S; Division of Reproductive and Medical Genetics, Department of Obstetrics & Gynecology and Women's Health, Montefiore Medical Center, Albert Einstein College of Medicine, New York, New York, USA., Park BH; Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, Tennessee, USA., Vijg J; Department of Genetics, Albert Einstein College of Medicine, New York, New York, USA.; Center for Single-Cell Omics, School of Public Health, Shanghai Jiao Tong University School of Medicine, Shanghai, China., Montagna C; Department of Genetics, Albert Einstein College of Medicine, New York, New York, USA.; Department of Radiation Oncology, Rutgers Cancer Institute of New Jersey, New Brunswick, New Jersey, USA.
Jazyk: angličtina
Zdroj: The Journal of clinical investigation [J Clin Invest] 2022 Mar 01; Vol. 132 (5).
DOI: 10.1172/JCI148113
Abstrakt: 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.
Databáze: MEDLINE