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

Breast Cancer Research

Zhiwei Liu¹  Dejing Pan¹  Fei Zhou¹  Xichun Hu²  Jian Zhang²  Jun Cao²  Yi Wang³  Xiaolin Wang³  Ying Yu³  Luyao Ren³  Tao Qing³  Yuanting Zheng³  Xiangnan Li³  Sibo Zhu³  Lei Zhang³  Ding Bao³  Jingcheng Yang³  Shangzi Wang³  Bingying Li³  Wanwan Hou³  Leming Shi⁴  Yangyang Qiu⁵  Jiaxue Wu⁵ 

[1]Cambridge-Suda Genomic Resource Center and Jiangsu Key Laboratory of Neuropsychiatric Diseases Research, Soochow University, Suzhou, China

[2]Department of Medical Oncology, Fudan University Shanghai Cancer Center, Shanghai, China

[3]State Key Laboratory of Genetic Engineering, School of Life Sciences and Shanghai Cancer Center, Fudan University, Shanghai, China

[4]State Key Laboratory of Genetic Engineering, School of Life Sciences and Shanghai Cancer Center, Fudan University, Shanghai, China

[5]Human Phenome Institute, Fudan University, Shanghai, China

[6]Fudan-Gospel Joint Research Center for Precision Medicine, Fudan University, Shanghai, China

[7]State Key Laboratory of Genetic Engineering, School of Life Sciences and Zhongshan Hospital, Fudan University, Shanghai, China

关键词: BARD1;    Rare mutation;    c.403G>A;    p.Asp135Asn;    Integrated genomics profiling;    Triple-negative breast cancer;    Irradiation;    DNA damage;    PARP inhibitor;    Functional assay;   

DOI  :  10.1186/s13058-021-01428-5

来源: Springer

【 摘 要 】

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.

【 授权许可】

CC BY