title: Molecular insights into the OGG1 gene, a cancer risk modifier in BRCA1 and BRCA2 mutations carriers.
abstract: We have recently shown that rs2304277 variant in the OGG1 glycosidase gene of the Base Excision Repair pathway can increase ovarian cancer risk in BRCA1 mutation carriers. In the present study, we aimed to explore the role of this genetic variant on different genome instability hallmarks to explain its association with cancer risk.We have evaluated the effect of this polymorphism on OGG1 transcriptional regulation and its contribution to telomere shortening and DNA damage accumulation. For that, we have used a series of 89 BRCA1 and BRCA2 mutation carriers, 74 BRCAX cases, 60 non-carrier controls and 23 lymphoblastoid cell lines (LCL) derived from BRCA1 mutation carriers and non-carriers.We have identified that this SNP is associated to a significant OGG1 transcriptional down regulation independently of the BRCA mutational status and that the variant may exert a synergistic effect together with BRCA1 or BRCA2 mutations on DNA damage and telomere shortening.These results suggest that this variant, could be associated to a higher cancer risk in BRCA1 mutation carriers, due to an OGG1 transcriptional down regulation and its effect on genome instability.
authors.affiliation: Human Genetics Group, Spanish National Cancer Research Center (CNIO), Madrid 28029, Spain.
authors.forename: Carlos
authors.initials: C
authors.lastname: Benitez-Buelga
authors.affiliation: Human Genetics Group, Spanish National Cancer Research Center (CNIO), Madrid 28029, Spain.
authors.forename: Tereza
authors.initials: T
authors.lastname: Vaclová
authors.affiliation: Human Genetics Group, Spanish National Cancer Research Center (CNIO), Madrid 28029, Spain.
authors.forename: Sofia
authors.initials: S
authors.lastname: Ferreira
authors.affiliation: Familial Cancer Clinical Unit, Spanish National Cancer Research Center (CNIO), Madrid 28029, Spain.|Spanish Network on Rare Diseases (CIBERER), Madrid 28029, Spain.
authors.forename: Miguel
authors.initials: M
authors.lastname: Urioste
authors.affiliation: Endocrine Cancer Group, Spanish National Cancer Research Center (CNIO), Madrid 28029, Spain.|Spanish Network on Rare Diseases (CIBERER), Madrid 28029, Spain.
authors.forename: Lucia
authors.initials: L
authors.lastname: Inglada-Perez
authors.affiliation: Telomere and Telomerase Group, Spanish National Cancer Research Center (CNIO), Madrid 28029, Spain.
authors.forename: Nora
authors.initials: N
authors.lastname: Soberón
authors.affiliation: Telomere and Telomerase Group, Spanish National Cancer Research Center (CNIO), Madrid 28029, Spain.
authors.forename: Maria A
authors.initials: MA
authors.lastname: Blasco
authors.affiliation: Human Genetics Group, Spanish National Cancer Research Center (CNIO), Madrid 28029, Spain.|Spanish Network on Rare Diseases (CIBERER), Madrid 28029, Spain.
authors.forename: Ana
authors.initials: A
authors.lastname: Osorio
authors.affiliation: Human Genetics Group, Spanish National Cancer Research Center (CNIO), Madrid 28029, Spain.|Spanish Network on Rare Diseases (CIBERER), Madrid 28029, Spain.
authors.forename: Javier
authors.initials: J
authors.lastname: Benitez
mesh_terms: D019313:BRCA1 Protein / Q000235:genetics*; D024682:BRCA2 Protein / Q000235:genetics*; D045647:DNA Glycosylases / Q000235:genetics*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005838:Genotype; D006801:Humans; D009154:Mutation; D010051:Ovarian Neoplasms / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D012307:Risk Factors
chemical_list: D019313:BRCA1 Protein; C492913:BRCA1 protein, human; D024682:BRCA2 Protein; C551750:BRCA2 protein, human; D045647:DNA Glycosylases; C479058:oxoguanine glycosylase 1, human
keywords: BRCA1 and BRCA2; DNA damage; OGG1 polymorfism; cancer risk modifier; telomere shortening