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.
Highlights
Carrying an inherited mutation in the BRCA1 or BRCA2 genes increases a woman's lifetime risk of developing breast and ovarian cancers there are considerable differences in disease manifestation
We have previously found that the OGG1 single nucleotide polymorphisms (SNPs) rs2304277may be a modifier of cancer risk in BRCA1 mutation carriers [5]
In this study we have shown how this variant can contribute to increase cancer risk in BRCA1 carriers, by reducing the mRNA OGG1 expression levels, increasing the DNA damage as a consequence of genomic instability generated, and shortening the telomeres in a synergic way with the BRCA1 mutation
Summary
Carrying an inherited mutation in the BRCA1 or BRCA2 genes increases a woman's lifetime risk of developing breast and ovarian cancers there are considerable differences in disease manifestation. In the context of BRCA1 and BRCA2 mutation carriers, it has been shown that other factors such as single nucleotide polymorphisms (SNPs) in genes from other DNA repair pathways could cause a higher genomic instability, increasing the cancer risk predisposition [3,4,5,6]. In this regard, a well-known synthetic lethal interaction is described between the BRCA1 and BRCA2 genes and the poly ADP ribose polymerase (PARP1), involved in the Base Excision Repair (BER) pathway [7]. In the presence of a defective BRCA1 or BRCA2 background, this accumulation of double-strand DNA breaks can persist and lead to cell cycle arrest or cell death; making BRCAdeficient cells extremely sensitive to PARP inhibitors (PARPi)
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