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A novel BRCA1 germline mutation promotes triple-negative breast cancer cells progression and enhances sensitivity to DNA damage agents

  • Author Footnotes
    1 These authors contributed equally to this work.
    Kun Xu
    Footnotes
    1 These authors contributed equally to this work.
    Affiliations
    Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China
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  • Author Footnotes
    1 These authors contributed equally to this work.
    Yaqin Shi
    Footnotes
    1 These authors contributed equally to this work.
    Affiliations
    Department of Medical Oncology, Medical School of Nanjing University, Nanjing 210002, China
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  • Author Footnotes
    1 These authors contributed equally to this work.
    Xin Wang
    Footnotes
    1 These authors contributed equally to this work.
    Affiliations
    Department of Medical Oncology, Medical School of Nanjing University, Nanjing 210002, China
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  • Yajuan Chen
    Affiliations
    Department of Medical Oncology, Jinling Hospital, Nanjing Medical University, Nanjing 210002, China
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  • Lin Tang
    Affiliations
    Department of Medical Oncology, Medical School of Nanjing University, Nanjing 210002, China
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  • Xiaoxiang Guan
    Correspondence
    Corresponding author at: Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing 210029, China.
    Affiliations
    Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China

    Department of Medical Oncology, Medical School of Nanjing University, Nanjing 210002, China

    Department of Medical Oncology, Jinling Hospital, Nanjing Medical University, Nanjing 210002, China
    Search for articles by this author
  • Author Footnotes
    1 These authors contributed equally to this work.

      Highlights

      • A nonsense mutation BRCA1 p.Trp372X was first identified in a pedigree.
      • BRCA1 p.Trp372X promotes BRCA wild-type TNBC cancer progression.
      • BRCA1 p.Trp372X sensitizes BRCA wild-type TNBC cells to DNA damage agents through impairing homologous recombination of BRCA1.

      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.

      Keywords

      Abbreviations:

      BIC (Breast Cancer Information Core), DSBs (Double strand damages), HER-2 (Human epidermal growth factor receptor 2), HR (Homologous recombination), TNBC (Triple negative breast cancer)
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