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

Abstract

Abstract 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<0.0045). TL was not associated to higher cancer risk in our FBOC series, pointing to this phenotype not as the cause of the cancer risk association, but maybe as a hallmark of a higher DNA damage environment when both genetic events are present in the cell. Using the LCL panel we were able to detect OGG1 mRNA down regulation due to the presence of the variant and a significant telomere shortening exclusively in the BRCA1 defective cells harboring the OGG1 SNP after 55 passages. The DNA damage studies, confirmed significant higher intensity levels of gammaH2AX in the damaged LCL harboring the SNP compared to those not harboring it (p<0.0001). These results, may explain the molecular insights behind this modifier variant. Under the prism of a deleterious interaction, in cells harboring mutations in BRCA genes, the presence of the SNP itself, seems to affect OGG1 mRNA down regulation. This could lead to a defective performance of the BER pathway that may lead to genome instability, characterized by higher gammaH2AX intensity in damaged cells and telomere shortening when both genetic events are present, and as consequence, higher cancer risk. 1. Osorio A, et al (2014) PLoS Genet Funding: J.B's laboratory, INNPRONTA 2012, Spanish Ministry of Health (PI12/00070) and (CIBERER). C.B is granted by PI12/00070 M.A.B.'s laboratory, Spanish Ministry of Science and Innovation (SAF2008-05384;2007-A-200950) (TELOMARKER), ERCA (GA#232854) Citation Format: Carlos Benitez-Buelga, Tereza Vaclova, María Sofia Ferreira, Nora Soberon, María Antonia Blasco, Ana Osorio, Javier Benitez. Molecular insights into OGG1 gene, a modifier of cancer risk in BRCA1 and BRCA2 mutations carriers. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2547.