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Scientific result | Cancer | Structural biology | DNA

What is the relationship between variants of the BRCA1 gene and susceptibility to cancer?

​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).

Published on 28 September 2018


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.

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