Clinical consequences of BRCA2 hypomorphism
Por:
Castells-Roca, L, Gutierrez-Enriquez, S, Bonache, S, Bogliolo, M, Carrasco, E, Aza-Carmona, M, Montalban, G, Munoz-Subirana, N, Pujol, R, Cruz, C, Llop-Guevara, A, Ramirez, MJ, Saura, C, Lasa, A, Serra, V, Diez, O, Balmana, J, Surralles, J
Publicada:
9 sep 2021
Resumen:
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.
Filiaciones:
Castells-Roca, L:
Hosp Santa Creu & Sant Pau, Genome Instabil & DNA Repair Syndromes Grp, Biomed Res Inst IIB St Pau, Barcelona, Spain
Hosp Santa Creu & Sant Pau, Join Unit UAB IR St Pau Genom Med, Biomed Res Inst IIB St Pau, Barcelona, Spain
Hosp Santa Creu & Sant Pau, Genet Dept, Barcelona, Spain
Gutierrez-Enriquez, S:
Vall dHebron Barcelona Hosp Campus, Hereditary Canc Genet Grp, Vall dHebron Inst Oncol VHIO, Barcelona, Spain
Bonache, S:
Vall dHebron Barcelona Hosp Campus, Hereditary Canc Genet Grp, Vall dHebron Inst Oncol VHIO, Barcelona, Spain
Bogliolo, M:
Hosp Santa Creu & Sant Pau, Genome Instabil & DNA Repair Syndromes Grp, Biomed Res Inst IIB St Pau, Barcelona, Spain
Hosp Santa Creu & Sant Pau, Join Unit UAB IR St Pau Genom Med, Biomed Res Inst IIB St Pau, Barcelona, Spain
Hosp Santa Creu & Sant Pau, Genet Dept, Barcelona, Spain
Ctr Biomed Network Res Rare Dis CIBERER U745, Barcelona, Spain
Carrasco, E:
Vall dHebron Barcelona Hosp Campus, Hereditary Canc Genet Grp, Vall dHebron Inst Oncol VHIO, Hosp Univ Vail dHebron, Barcelona, Spain
Aza-Carmona, M:
Hosp Santa Creu & Sant Pau, Genome Instabil & DNA Repair Syndromes Grp, Biomed Res Inst IIB St Pau, Barcelona, Spain
Hosp Santa Creu & Sant Pau, Join Unit UAB IR St Pau Genom Med, Biomed Res Inst IIB St Pau, Barcelona, Spain
Montalban, G:
Vall dHebron Barcelona Hosp Campus, Hereditary Canc Genet Grp, Vall dHebron Inst Oncol VHIO, Barcelona, Spain
Univ Laval, CHU Quebec, Res Ctr, Oncol Div, 9 Rue McMahon, Quebec City, PQ G1R 3S3, Canada
Munoz-Subirana, N:
Hosp Santa Creu & Sant Pau, Genome Instabil & DNA Repair Syndromes Grp, Biomed Res Inst IIB St Pau, Barcelona, Spain
Hosp Santa Creu & Sant Pau, Join Unit UAB IR St Pau Genom Med, Biomed Res Inst IIB St Pau, Barcelona, Spain
Pujol, R:
Hosp Santa Creu & Sant Pau, Genome Instabil & DNA Repair Syndromes Grp, Biomed Res Inst IIB St Pau, Barcelona, Spain
Hosp Santa Creu & Sant Pau, Join Unit UAB IR St Pau Genom Med, Biomed Res Inst IIB St Pau, Barcelona, Spain
Hosp Santa Creu & Sant Pau, Genet Dept, Barcelona, Spain
Ctr Biomed Network Res Rare Dis CIBERER U745, Barcelona, Spain
Cruz, C:
Vall dHebron Barcelona Hosp Campus, Expt Therapeut Grp, Vall dHebron Inst Oncol VHIO, Barcelona, Spain
Llop-Guevara, A:
Vall dHebron Barcelona Hosp Campus, Expt Therapeut Grp, Vall dHebron Inst Oncol VHIO, Barcelona, Spain
Ramirez, MJ:
Hosp Santa Creu & Sant Pau, Genome Instabil & DNA Repair Syndromes Grp, Biomed Res Inst IIB St Pau, Barcelona, Spain
Hosp Santa Creu & Sant Pau, Join Unit UAB IR St Pau Genom Med, Biomed Res Inst IIB St Pau, Barcelona, Spain
Hosp Santa Creu & Sant Pau, Genet Dept, Barcelona, Spain
Ctr Biomed Network Res Rare Dis CIBERER U745, Barcelona, Spain
Saura, C:
Vall dHebron Barcelona Hosp Campus, Breast Canc & Melanoma Grp, Vall dHebron Inst Oncol VHIO, Hosp Univ Vall dHebron, Barcelona, Spain
Lasa, A:
Hosp Santa Creu & Sant Pau, Genet Dept, Barcelona, Spain
Ctr Biomed Network Res Rare Dis CIBERER U705, Barcelona, Spain
Serra, V:
Vall dHebron Barcelona Hosp Campus, Expt Therapeut Grp, Vall dHebron Inst Oncol VHIO, Barcelona, Spain
Diez, O:
Vall dHebron Barcelona Hosp Campus, Hereditary Canc Genet Grp, Vall dHebron Inst Oncol VHIO, Hosp Univ Vail dHebron, Barcelona, Spain
Balmana, J:
Vall dHebron Barcelona Hosp Campus, Hereditary Canc Genet Grp, Vall dHebron Inst Oncol VHIO, Hosp Univ Vail dHebron, Barcelona, Spain
Surralles, J:
Hosp Santa Creu & Sant Pau, Genome Instabil & DNA Repair Syndromes Grp, Biomed Res Inst IIB St Pau, Barcelona, Spain
Hosp Santa Creu & Sant Pau, Join Unit UAB IR St Pau Genom Med, Biomed Res Inst IIB St Pau, Barcelona, Spain
Hosp Santa Creu & Sant Pau, Genet Dept, Barcelona, Spain
Ctr Biomed Network Res Rare Dis CIBERER U745, Barcelona, Spain
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