5 research outputs found
Clinical and molecular description of 19 patients with GATAD2B-Associated Neurodevelopmental Disorder (GAND)
International audienc
Combining Homologous Recombination and Phosphopeptide-binding Data to Predict the Impact of BRCA1 BRCT Variants on Cancer Risk
WOS:000454834200006International audienceBRCA1 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, 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 on the basis of 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. Implications: The analysis of the current study on BRCA1 structural and functional defects on cancer risk and classification presented may improve clinical interpretation and therapeutic selection
Genetic architectures of proximal and distal colorectal cancer are partly distinct
Objective An understanding of the etiologic heterogeneity of colorectal
cancer (CRC) is critical for improving precision prevention, including
individualized screening recommendations and the discovery of novel drug
targets and repurposable drug candidates for chemoprevention. Known
differences in molecular characteristics and environmental risk factors
among tumors arising in different locations of the colorectum suggest
partly distinct mechanisms of carcinogenesis. The extent to which the
contribution of inherited genetic risk factors for CRC differs by
anatomical subsite of the primary tumor has not been examined.
Design To identify new anatomical subsite-specific risk loci, we
performed genome-wide association study (GWAS) meta-analyses including
data of 48 214 CRC cases and 64 159 controls of European ancestry. We
characterised effect heterogeneity at CRC risk loci using multinomial
modelling.
Results We identified 13 loci that reached genome-wide significance
(p<5x10(-8)) and that were not reported by previous GWASs for overall
CRC risk. Multiple lines of evidence support candidate genes at several
of these loci. We detected substantial heterogeneity between anatomical
subsites. Just over half (61) of 109 known and new risk variants showed
no evidence for heterogeneity. In contrast, 22 variants showed
association with distal CRC (including rectal cancer), but no evidence
for association or an attenuated association with proximal CRC. For two
loci, there was strong evidence for effects confined to proximal colon
cancer.
Conclusion Genetic architectures of proximal and distal CRC are partly
distinct. Studies of risk factors and mechanisms of carcinogenesis, and
precision prevention strategies should take into consideration the
anatomical subsite of the tumour