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oai:recercat.cat:11351/74312025-05-03T03:20:12Zcom_2072_378070com_2072_378040col_2072_378092

urn:hdl:11351/7431 Clinical consequences of BRCA2 hypomorphism Castells-Roca, Laia Gutierrez Enriquez, Sara Bonache Real, Sandra Carrasco López, Estela Aza-Carmona, Miriam Montalban Canudas, Gemma Cruz Zambrano, Cristina Llop Guevara, Alba Serra Elizalde, Violeta Diez Gibert, Orland Balmaña Gelpí, Judith Saura Manich, Cristina Bogliolo, Massimo Mama - Càncer Anèmia de Fanconi Gens del càncer DISEASES::Neoplasms::Neoplasms by Site::Breast Neoplasms CHEMICALS AND DRUGS::Amino Acids, Peptides, and Proteins::Proteins::Fanconi Anemia Complementation Group Proteins::BRCA2 Protein DISEASES::Hemic and Lymphatic Diseases::Hematologic Diseases::Anemia::Anemia, Aplastic::Anemia, Hypoplastic, Congenital::Fanconi Anemia ENFERMEDADES::neoplasias::neoplasias por localización::neoplasias de la mama COMPUESTOS QUÍMICOS Y DROGAS::aminoácidos, péptidos y proteínas::proteínas::proteínas de grupos de complementación de la anemia de Fanconi::proteína BRCA2 ENFERMEDADES::enfermedades hematológicas y linfáticas::enfermedades hematológicas::anemia::anemia aplásica::anemia hipoplásica congénita::anemia de Fanconi Breast cancer; Cancer genetics Cáncer de mama; Genética del cáncer Càncer de mama; Genètica del càncer 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. 2022-05-02T12:38:36Z 2022-05-02T12:38:36Z 2021-09-09 info:eu-repo/semantics/article info:eu-repo/semantics/publishedVersion npj Breast Cancer;7 https://doi.org/10.1038/s41523-021-00322-9 info:eu-repo/grantAgreement/ES/PE2013-2016/PI16%2F01218 info:eu-repo/grantAgreement/ES/PE2017-2020/PI19%2F01303 info:eu-repo/grantAgreement/ES/1PN/2008-2011/PI12%2F02606 info:eu-repo/grantAgreement/ES/PE2013-2016/PI17%2F01080 info:eu-repo/grantAgreement/EC/H2020/665919 Attribution 4.0 International http://creativecommons.org/licenses/by/4.0/ info:eu-repo/semantics/openAccess Nature Research Scientia