Abstract 2547: Molecular insights into OGG1 gene, a modifier of cancer risk in BRCA1 and BRCA2 mutations carriers

Oxidative stress is a source of DNA damage which can lead to genomic instability and telomere shortening. The OGG1 glycosidase plays an important role in the Base Excision Repair (BER) pathway that counteracts the oxidative DNA damage caused by endogenous cell stress. Recently, we have demonstrated that a single nucleotide polymorphism (SNP) in the OGG1 gene can modify cancer risk in carriers of germline mutations in the BRCA1 and BRCA2 genes1. Hence, we aimed to explore the possible role of this variant in DNA damage and telomere shortening to explain the association of this cancer risk variant. We used 2 independent set of samples with a heterogeneous BRCA mutational status. First of all, a familiar breast and ovarian cancer (FBOC) set of 154 BRCA patients (BRCA1, BRCA2 and BRCAX) and 68 controls, were used to measure the mRNA OGG1 expression levels in blood and the leukocyte telomere length (TL). Second, we used a panel of 23 Lymphoblastoid Cell Lines (LCL) from patients harboring germline mutations in BRCA1 and non-carrier controls to validate previous results regarding OGG1 mRNA expression levels and telomere shortening. Additionally we measured gammaH2AX intensity levels in LCL to evaluate the role of the SNP on DNA damage. In the FBOC series, we found that the carriers of the variant had significant decreased expression levels of the OGG1 transcript compared with the non-carriers (p = 0.013). Regarding TL studies, we found that the variant may exert a synergistic effect together with BRCA1/2 mutations on telomere shortening (p