Abstract
Breast cancer is the most frequent malignancy and the second leading cause of cancer death in female worldwide. Compared with general population, patients with mutations in BRCA1 and BRCA2 genes confer approximately 10-fold increased risk of breast cancer. In this study, we conducted whole-exome sequencing to identify the disease-associated genes in a specific pedigree, in which at least eight individuals were diagnosed with cancers, including breast cancer, urothelial cancer, uterine cancer and colorectal cancer. Furthermore, a nonsense mutation BRCA1 p.Trp372X was identified in the proband. The Sanger sequencing data has validated the same nonsense mutation in other 4 cancer patients and 3 normal family members. Additionally, functional experiments detected that this mutation was implicated in TNBC progression, manifesting as increased cell proliferation and migration. Cells with this mutation displayed impaired recruitment of RAD51 foci and unrepaired DNA damage, potentiating drug sensitivity to PARP inhibitor and cisplatin, both in the settings of combination use or monotherapy. On the basis of its occurrence in hereditary breast cancer and its identification in pedigree, as well as its function as a disruption of BRCA1, this mutation is critical to breast cancer predisposition and progression. Patients carrying this mutation may benefit from DNA damaging treatment regimens. Conclusively, we firstly reported this nonsense mutation in family pedigree and validated its pathogenicity through in vitro functional experiments.