Clinical consequences of BRCA2 hypomorphism

The tumor suppressor FANCD1/BRCA2 is crucial for DNA homologous recombination repair (HRR). BRCA2 biallelic pathogenic variants result in a severe form of Fanconi anemia (FA) syndrome, whereas monoallelic pathogenic variants cause mainly hereditary breast and ovarian cancer predisposition. For decad...

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Bibliographic Details
Published in:NPJ breast cancer 2021-09, Vol.7 (1), p.117-117, Article 117
Main Authors: Castells-Roca, Laia, Gutiérrez-Enríquez, Sara, Bonache, Sandra, Bogliolo, Massimo, Carrasco, Estela, Aza-Carmona, Miriam, Montalban, Gemma, Muñoz-Subirana, Núria, Pujol, Roser, Cruz, Cristina, Llop-Guevara, Alba, Ramírez, María J., Saura, Cristina, Lasa, Adriana, Serra, Violeta, Diez, Orland, Balmaña, Judith, Surrallés, Jordi
Format: Article
Language:English
Subjects:
631/67/68
692/699/67/1347
Anemia
Biomedical and Life Sciences
Biomedicine
Brain cancer
Breast cancer
Cancer Research
Cancer therapies
Case Report
Cell Biology
Cell cycle
Chemotherapy
Chromosomes
DNA damage
DNA repair
Fibroblasts
Hospitals
Human Genetics
Leukemia
Lymphocytes
Medical research
Oncology
Ovarian cancer
Patients
Tumors
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Summary:The tumor suppressor FANCD1/BRCA2 is crucial for DNA homologous recombination repair (HRR). BRCA2 biallelic pathogenic variants result in a severe form of Fanconi anemia (FA) syndrome, whereas monoallelic pathogenic variants cause mainly hereditary breast and ovarian cancer predisposition. For decades, the co-occurrence in trans with a clearly pathogenic variant led to assume that the other allele was benign. However, here we show a patient with biallelic BRCA2 (c.1813dup and c.7796 A > G) diagnosed at age 33 with FA after a hypertoxic reaction to chemotherapy during breast cancer treatment. After DNA damage, patient cells displayed intermediate chromosome fragility, reduced survival, cell cycle defects, and significantly decreased RAD51 foci formation. With a newly developed cell-based flow cytometric assay, we measured single BRCA2 allele contributions to HRR, and found that expression of the missense allele in a BRCA2 KO cellular background partially recovered HRR activity. Our data suggest that a hypomorphic BRCA2 allele retaining 37–54% of normal HRR function can prevent FA clinical phenotype, but not the early onset of breast cancer and severe hypersensitivity to chemotherapy.
ISSN:2374-4677
2374-4677
DOI:10.1038/s41523-021-00322-9