Functional consequences of a rare missense BARD1 c.403G>A germline mutation identified in a triple-negative breast cancer patient

• Published in: Breast cancer research : BCR 2021-05, Vol.23 (1), p.53-53, Article 53
• Main Authors: Zheng, Yuanting, Li, Bingying, Pan, Dejing, Cao, Jun, Zhang, Jian, Wang, Xiaolin, Li, Xiangnan, Hou, Wanwan, Bao, Ding, Ren, Luyao, Yang, Jingcheng, Wang, Shangzi, Qiu, Yangyang, Zhou, Fei, Liu, Zhiwei, Zhu, Sibo, Zhang, Lei, Qing, Tao, Wang, Yi, Yu, Ying, Wu, Jiaxue, Hu, Xichun, Shi, Leming
• Format: Article
• Language: English
• Subjects: Age; Amino acids; Anemia; Animal models; Animals; BARD1; BRCA1 protein; Breast cancer; c.403G>A; Cancer therapies; Cell culture; Cell growth; Clinical medicine; CRISPR; DNA damage; DNA Damage - genetics; Female; Gene Expression Profiling; Genetic counseling; Genetic Predisposition to Disease - genetics; Genomes; Genomics; Germ-Line Mutation; Humans; Integrated genomics profiling; Ionizing radiation; Metastasis; Mice; Mutants; Mutation; Mutation, Missense; p.Asp135Asn; Patients; Poly(ADP-ribose) polymerase; Poly(ADP-ribose) Polymerase Inhibitors - therapeutic use; Proteins; Rad51 Recombinase - metabolism; Radiation therapy; Radiation Tolerance - genetics; Rare mutation; Short Report; Triple Negative Breast Neoplasms - drug therapy; Triple Negative Breast Neoplasms - genetics; Triple Negative Breast Neoplasms - metabolism; Triple-negative breast cancer; Tumor Suppressor Proteins - genetics; Tumor Suppressor Proteins - metabolism; Ubiquitin-Protein Ligases - genetics; Ubiquitin-Protein Ligases - metabolism
• ISSN: 1465-542X; 1465-5411; 1465-542X
• DOI: 10.1186/s13058-021-01428-5

We identified a rare missense germline mutation in BARD1 (c.403G>A or p.Asp135Asn) as pathogenic using integrated genomics and transcriptomics profiling of germline and tumor samples from an early-onset triple-negative breast cancer patient who later was administrated with a PARP inhibitor for 2 months. We demonstrated in cell and mouse models that, compared to the wild-type, (1) c.403G>A mutant cell lines were more sensitive to irradiation, a DNA damage agent, and a PARP inhibitor; (2) c.403G>A mutation inhibited interaction between BARD1 and RAD51 (but not BRCA1); and (3) c.403G>A mutant mice were hypersensitive to ionizing radiation. Our study shed lights on the clinical interpretation of rare germline mutations of BARD1.