Clinical consequences of BRCA2 hypomorphism

Abstract 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....

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Autores principales:	Laia Castells-Roca, Sara Gutiérrez-Enríquez, Sandra Bonache, Massimo Bogliolo, Estela Carrasco, Miriam Aza-Carmona, Gemma Montalban, Núria Muñoz-Subirana, Roser Pujol, Cristina Cruz, Alba Llop-Guevara, María J. Ramírez, Cristina Saura, Adriana Lasa, Violeta Serra, Orland Diez, Judith Balmaña, Jordi Surrallés
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
Acceso en línea:	https://doaj.org/article/f5fbf0683dd64720a1c4fee28554ad68
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spelling	oai:doaj.org-article:f5fbf0683dd64720a1c4fee28554ad682021-12-02T14:55:14ZClinical consequences of BRCA2 hypomorphism10.1038/s41523-021-00322-92374-4677https://doaj.org/article/f5fbf0683dd64720a1c4fee28554ad682021-09-01T00:00:00Zhttps://doi.org/10.1038/s41523-021-00322-9https://doaj.org/toc/2374-4677Abstract 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.Laia Castells-RocaSara Gutiérrez-EnríquezSandra BonacheMassimo BoglioloEstela CarrascoMiriam Aza-CarmonaGemma MontalbanNúria Muñoz-SubiranaRoser PujolCristina CruzAlba Llop-GuevaraMaría J. RamírezCristina SauraAdriana LasaVioleta SerraOrland DiezJudith BalmañaJordi SurrallésNature PortfolioarticleNeoplasms. Tumors. Oncology. Including cancer and carcinogensRC254-282ENnpj Breast Cancer, Vol 7, Iss 1, Pp 1-9 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
spellingShingle	Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282 Laia Castells-Roca Sara Gutiérrez-Enríquez Sandra Bonache Massimo Bogliolo Estela Carrasco Miriam Aza-Carmona Gemma Montalban Núria Muñoz-Subirana Roser Pujol Cristina Cruz Alba Llop-Guevara María J. Ramírez Cristina Saura Adriana Lasa Violeta Serra Orland Diez Judith Balmaña Jordi Surrallés Clinical consequences of BRCA2 hypomorphism
description	Abstract 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.
format	article
author	Laia Castells-Roca Sara Gutiérrez-Enríquez Sandra Bonache Massimo Bogliolo Estela Carrasco Miriam Aza-Carmona Gemma Montalban Núria Muñoz-Subirana Roser Pujol Cristina Cruz Alba Llop-Guevara María J. Ramírez Cristina Saura Adriana Lasa Violeta Serra Orland Diez Judith Balmaña Jordi Surrallés
author_facet	Laia Castells-Roca Sara Gutiérrez-Enríquez Sandra Bonache Massimo Bogliolo Estela Carrasco Miriam Aza-Carmona Gemma Montalban Núria Muñoz-Subirana Roser Pujol Cristina Cruz Alba Llop-Guevara María J. Ramírez Cristina Saura Adriana Lasa Violeta Serra Orland Diez Judith Balmaña Jordi Surrallés
author_sort	Laia Castells-Roca
title	Clinical consequences of BRCA2 hypomorphism
title_short	Clinical consequences of BRCA2 hypomorphism
title_full	Clinical consequences of BRCA2 hypomorphism
title_fullStr	Clinical consequences of BRCA2 hypomorphism
title_full_unstemmed	Clinical consequences of BRCA2 hypomorphism
title_sort	clinical consequences of brca2 hypomorphism
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/f5fbf0683dd64720a1c4fee28554ad68
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Clinical consequences of BRCA2 hypomorphism

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