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Scientific result | Cancer | Structural biology | DNA
Research Teams from the Curie Institute, the Gustave Roussy Institute, as well as the biophysics teams from the Institute of Chemistry of Natural Substances and SB2SM (I2BC@Saclay) met to systematically identify structural defects and BRCA1 proteins encoded by variants of the BRCA1 gene, a gene predisposing to breast and ovarian cancer. Their results make it possible to propose a classification of these variants (neutral versus causal).
BRCA1 mutations have been identified that increase the risk of developing hereditary breast and ovarian cancers. Genetic screening is now offered to patients with a family history of cancer, in order to adapt their treatment and the management of their relatives. However, a large number of BRCA1 variants of uncertain significance (VUS) are detected. To better understand the significance of these variants, a high-throughput structural and functional analysis was performed on a large set of BRCA1-VUS. Information on both cellular localization and homology-directed DNA-repair (HR) capacity was obtained for 78 BRCT-missense variants in the UMD-BRCA1 database and measurement of the structural stability and phosphopeptide-binding capacities was performed for 42 mutated BRCT-domains. This extensive and systematic analysis revealed that most characterized causal variants affect BRCT-domain solubility in bacteria and all impair BRCA1 HR activity in cells. Furthermore, binding to a set of 5 different phosphopeptides was tested: all causal variants showed phosphopeptide-binding defects and no neutral variant showed such defects. A classification is presented based on mutated BRCT-domain solubility, phosphopeptide-binding properties, and VUS HR-capacity. These data suggest that HR-defective variants, which present, in addition, BRCT-domains either insoluble in bacteria or defective for phosphopeptide-binding, lead to an increased cancer risk. Furthermore, the data suggest that variants with a WT HR-activity and whose BRCT-domains bind with a WT affinity to the 5 phosphopeptides are neutral. The case of variants with WT HR-activity and defective phosphopeptide-binding should be further characterized, as this last functional defect might be sufficient per se to lead to tumorigenesis.Read the French version.
Combining Homologous Recombination and phosphopeptide-binding assays to predict the impact of BRCA1 BRCT variants on cancer risk. A. Petitalot, E. Dardillac, E. Jacquet, N. Nhiri, J. Guirouilh-Barbat, P. Julien, I. Bouazzaoui, D. Bonte, J. Feunteun, J. A. Schnell, P. Lafitte, J.C. Aude, UNICANCER Genetic Group BRCA network, C. Noguès, E. Rouleau, R. Lidereau, B. S. Lopez, S. Zinn-Justin and S. M. Caputo. Classification of BRCA1 BRCT missense VUS. (2018). Molecular Cancer Research http://dx.doi.org/10.1158/1541-7786.MCR-17-0357
CEA is a French government-funded technological research organisation in four main areas: low-carbon energies, defense and security, information technologies and health technologies. A prominent player in the European Research Area, it is involved in setting up collaborative projects with many partners around the world.