Data from A BRCA1 Coiled-Coil Domain Variant Disrupting PALB2 Interaction Promotes the Development of Mammary Tumors and Confers a Targetable Defect in Homologous Recombination Repair
Abstract
Abstract The BRCA1 tumor suppressor gene encodes a multidomain protein for which several functions have been described. These include a key role in homologous recombination repair (HRR) of DNA double-strand breaks, which is shared with two other high-risk hereditary breast cancer suppressors, BRCA2 and PALB2. Although both BRCA1 and BRCA2 interact with PALB2, BRCA1 missense variants affecting its PALB2-interacting coiled-coil domain are considered variants of uncertain clinical significance (VUS). Using genetically engineered mice, we show here that a BRCA1 coiled-coil domain VUS, Brca1 p.L1363P, disrupts the interaction with PALB2 and leads to embryonic lethality. Brca1 p.L1363P led to a similar acceleration in the development of Trp53-deficient mammary tumors as Brca1 loss, but the tumors showed distinct histopathologic features, with more stable DNA copy number profiles in Brca1 p.L1363P tumors. Nevertheless, Brca1 p.L1363P mammary tumors were HRR incompetent and responsive to cisplatin and PARP inhibition. Overall, these results provide the first direct evidence that a BRCA1 missense variant outside of the RING and BRCT domains increases the risk of breast cancer. Significance: These findings reveal the importance of a patient-derived BRCA1 coiled-coil domain sequence variant in embryonic development, mammary tumor suppression, and therapy response. See related commentary by Mishra et al., p. 6080
Authors 24
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The Netherlands Cancer Institute · Oncode Institute
Affiliation as printed
Oncode Institute and Division of Molecular Pathology, The Netherlands Cancer Institute, Amsterdam, the Netherlands
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Erasmus MC · Erasmus MC Cancer Institute
Affiliation as printed
Department of Molecular Genetics, Erasmus MC Cancer Institute, Erasmus University Medical Center, Rotterdam, the Netherlands
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Erasmus MC · Erasmus MC Cancer Institute
Affiliation as printed
Department of Molecular Genetics, Erasmus MC Cancer Institute, Erasmus University Medical Center, Rotterdam, the Netherlands
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Erasmus MC · Erasmus MC Cancer Institute
Affiliation as printed
Department of Molecular Genetics, Erasmus MC Cancer Institute, Erasmus University Medical Center, Rotterdam, the Netherlands
Department of Radiology and Nuclear Medicine, Erasmus University Medical Center, Rotterdam, the Netherlands
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Leiden University Medical Center
Affiliation as printed
Department of Human Genetics, Leiden University Medical Center, Leiden, the Netherlands
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The Netherlands Cancer Institute · Oncode Institute
Affiliation as printed
Oncode Institute and Division of Molecular Pathology, The Netherlands Cancer Institute, Amsterdam, the Netherlands
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The Netherlands Cancer Institute · Oncode Institute
Affiliation as printed
Oncode Institute and Division of Molecular Carcinogenesis, The Netherlands Cancer Institute, Amsterdam, the Netherlands
Oncode Institute and Division of Molecular Pathology, The Netherlands Cancer Institute, Amsterdam, the Netherlands
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The Netherlands Cancer Institute · Oncode Institute
Affiliation as printed
Oncode Institute and Division of Molecular Pathology, The Netherlands Cancer Institute, Amsterdam, the Netherlands
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The Netherlands Cancer Institute · Oncode Institute
Affiliation as printed
Oncode Institute and Division of Molecular Pathology, The Netherlands Cancer Institute, Amsterdam, the Netherlands
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The Netherlands Cancer Institute · Oncode Institute
Affiliation as printed
Oncode Institute and Division of Molecular Pathology, The Netherlands Cancer Institute, Amsterdam, the Netherlands
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Erasmus MC · Erasmus MC Cancer Institute
Affiliation as printed
Department of Molecular Genetics, Erasmus MC Cancer Institute, Erasmus University Medical Center, Rotterdam, the Netherlands
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The Netherlands Cancer Institute · Oncode Institute
Affiliation as printed
Oncode Institute and Division of Molecular Pathology, The Netherlands Cancer Institute, Amsterdam, the Netherlands
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The Netherlands Cancer Institute
Affiliation as printed
Experimental Animal Pathology, The Netherlands Cancer Institute, Amsterdam, the Netherlands
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The Netherlands Cancer Institute
Affiliation as printed
Preclinical Inter-vention Unit, Mouse Clinic for Cancer and Aging (MCCA), The Netherlands Cancer Institute, Amsterdam, the Netherlands
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The Netherlands Cancer Institute
Affiliation as printed
Preclinical Inter-vention Unit, Mouse Clinic for Cancer and Aging (MCCA), The Netherlands Cancer Institute, Amsterdam, the Netherlands
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The Netherlands Cancer Institute
Affiliation as printed
Transgenic Core Facility, Mouse Clinic for Cancer and Aging (MCCA), The Netherlands Cancer Institute, Amster-dam, the Netherlands
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The Netherlands Cancer Institute
Affiliation as printed
Transgenic Core Facility, Mouse Clinic for Cancer and Aging (MCCA), The Netherlands Cancer Institute, Amster-dam, the Netherlands
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Affiliation as printed
Department of Radiation Oncology, Rutgers Cancer Institute of New Jersey, New Brunswick, New Jersey
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Erasmus MC · Erasmus MC Cancer Institute
Affiliation as printed
Department of Molecular Genetics, Erasmus MC Cancer Institute, Erasmus University Medical Center, Rotterdam, the Netherlands
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Erasmus MC · Erasmus MC Cancer Institute · Erasmus University Rotterdam
Affiliation as printed
Department of Molecular Genetics, Erasmus MC Cancer Institute, Erasmus University Medical Center, Rotterdam, the Netherlands
Department of Radiation Oncology, Department of Vascular Surgery, Erasmus University Medical Center, Rotterdam, the Netherlands
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Leiden University Medical Center
Affiliation as printed
Department of Human Genetics, Leiden University Medical Center, Leiden, the Netherlands
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Erasmus MC · Erasmus MC Cancer Institute
Affiliation as printed
Department of Molecular Genetics, Erasmus MC Cancer Institute, Erasmus University Medical Center, Rotterdam, the Netherlands
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The Netherlands Cancer Institute · Oncode Institute
Affiliation as printed
Oncode Institute and Division of Molecular Pathology, The Netherlands Cancer Institute, Amsterdam, the Netherlands
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Erasmus MC · The Netherlands Cancer Institute · Oncode Institute · Erasmus MC Cancer Institute
Affiliation as printed
Department of Molecular Genetics, Erasmus MC Cancer Institute, Erasmus University Medical Center, Rotterdam, the Netherlands
Oncode Institute and Division of Molecular Pathology, The Netherlands Cancer Institute, Amsterdam, the Netherlands
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