Clinical consequences of BRCA2 hypomorphism
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, Marı́a José Ramı́rez, Cristina Saura, Adriana Lasa, Violeta Serra, Orland Dı́ez, Judith Balmañà, Jordi Surrallés
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.