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)To read this article in full you will need to make a payment
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Article info
Publication history
Published online: August 23, 2019
Accepted:
August 21,
2019
Received in revised form:
July 28,
2019
Received:
June 11,
2019
Identification
Copyright
© 2019 Elsevier Inc. All rights reserved.
