Título:
|
Clinical consequences of BRCA2 hypomorphism
|
Autor/a:
|
Castells-Roca, Laia; Gutiérrez-Enríquez, Sara; Bonache, Sandra; Bogliolo, Massimo; Carrasco, E.; Aza-Carmona, Miriam; Montalban, G.; Muñoz-Subirana, N.; Pujol, Roser; Cruz Zambrano, Cristina; Llop-Guevara, A.; Ramírez de Haro, Ma. José; Saura, Cristina; Lasa, Adriana; Serra, V.; Diez, Orland; Balmaña Gelpí, Judith; Surrallés i Calonge, Jordi; Universitat Autònoma de Barcelona
|
Abstract:
|
Altres ajuts: Asociación Española contra el Cáncer (LABAE16020PORTT) |
Abstract:
|
Altres ajuts: Asociación Española contra el Cáncer (ERAPERMED2019-215) |
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. |
Derechos:
|
open access
Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.
https://creativecommons.org/licenses/by/4.0/ |
Tipo de documento:
|
Article |
Editor:
|
|
Compartir:
|
|
Uri:
|
https://ddd.uab.cat/record/269625
|