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

Yuanting Zheng,Ji Cao ,Shangzi Wang,Xichun Hu,Yi Wang,Lei Zhang,Yangyang Qiu,Jingcheng Yang,Xiangnan Li,Jian Zhang,Tao Qing,Zhiwei Liu,Ying Yu,Luyao Ren,Dandan Pan ,Ding Bao,Fei Zhou,Xiaolin Wang,Bingying Li,Wanwan Hou,Jiaxue Wu,Sibo Zhu,Leming Shi

doi:10.1186/s13058-021-01428-5

Abstract

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.

Highlights

We identified a rare missense germline mutation in BRCA1-associated ring domain 1 (BARD1) (c.403G>A or p.Asp135Asn) as pathogenic using integrated genomics and transcriptomics profiling of germline and tumor samples from an early-onset triplenegative breast cancer patient who later was administrated with a Poly ADP-ribose polymerase (PARP) inhibitor for 2 months
Computational analysis of the genomics profiling from the patient’s tumor samples showed that the patient’s tumor exhibited extensive copy number changes, loss of heterozygosity, and large-scale structural variations across the entire genome (Fig. 1d), indicating a typical genomic mutational signature resulting from deficiency in homologous recombination DNA damage repair [12]
The mutation profile of BARD1 in the Fudan University Shanghai Cancer Center (FUSCC) TNBC cohort is shown in Fig. 1f, indicating that the germline mutation rate in BARD1 is low and the mutation loci were heterogeneous

Summary

Introduction

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 triplenegative breast cancer patient who later was administrated with a PARP inhibitor for 2 months. (See figure on previous page.) Fig. 1 Genomic and transcriptomic profiling reveals a highly conserved, rare, and potentially pathogenic germline mutation (c.403G>A) of BARD1 in an early-onset TNBC patient that displayed a homologous recombination deficiency (HRD) somatic mutational signature. F Somatic and germline mutation profiles of BARD1 in the FUSCC cohort.

Results

Conclusion