IP: Dr. Eladio Andrés Velasco Sampedro

Resumen del proyecto: Transcription and pre-mRNA processing (splicing) are subject to a strict control by regulator proteins and specific sequences in the promoter (binding of transcription factors) and pre-mRNA (splicing enhancers/silencers). Any DNA variant affecting such motifs can alter gene expression and be correlated with a disease. In fact, previous studies of our group showed that one third of deleterious mutations of BRCA1/BRCA2 induced aberrant splicing in Hereditary Breast Ovarian Cancer (HBOC). Our core objective is to determine the association between alterations of expression of both genes and susceptibility to breast/ovarian cancer. Specific objectives: 1) Functional analysis of promoter regions and transcriptional alterations of BRCA1 and BRCA2 in HBOC; 2) Association between aberrant splicing of BRCA1/BRCA2 and HBOC; 3) Regulation of premRNA processing of large exons of BRCA1 (exon 11) and BRCA2 (exons 10 and 11) and implications in HBOC. Methodology: HBOC patients will come from the Genetic Counselling Units of Castilla y León, data of DNA variants will be obtained from the International databases. Sequences and DNA variants will be analyzed with the programs TRANSFAC, TFSearch and Jaspar (promoters) and NNSPLICE and HSF (splicing). Functional assays of transcription and splicing will be carried out by promoter constructs coupled to a Luciferase reporter gene and hybrid minigenes in the splicing vector pSAD, respectively. The promoter regions of both genes will be sequenced in 200 patients.

Entidad financiadora: Instituto de Salud Carlos III