• cell
• LoH
• methylation
• mutation

BRCA1 acts a tumor suppressor gene and germ-line mutations which disrupt its functions culminate, after the loss of the wild type allele, in breast and ovarian cancer development. Although the precise biochemical functions of BRCA1 relevant for tumor suppression still remains to be clarified, it has been demonstrated to play a role in several cellular processes including: DNA DSBs repair, transcriptional regulation, chromatin remodeling, cell cycle checkpoints, ubiquitination and centrosome replication.
An increasing number of mutations leading to an amino acidic substitution in the protein (missense mutations) have been identified in hereditary breast/ovarian cancer patients and the pathogenetic role of such missense mutations remains largely undefined. We studied some BRCA1 variants of uncertain significance (VUSs) both by in vivo analysis and by in vitro analysis. In particular we carried out an in vivo molecular study on the tumor tissue from patients carrier of the VUSs and we performed three in vitro functional assays based on two BRCA1 cellular function:
the repair of DNA double strand break by Homologous Recombination and Non Homologous End Joining;
the transcriptional control.
It is important to perform systematic studies of the VUSs to assess pathogenicity of these variants found during genetic testing for BRCA1 hereditary breast and ovarian cancers.