Resumen de Functional validation of DNA glycosylases as cancer risk modifiers in BRCA1 and BRCA2 mutation carriers.: Potential use of OGG1 inhibitors as a novel strategy for cancer treatment
Women carrying germline deleterious mutations in the BRCA1 and BRCA2 genes have a high lifetime risk of developing breast and ovarian cancer. However, mutation carriers show considerable differences in disease manifestation, and this suggests the existence of genetic or environmental factors that modify the risk of cancer development. The identification of these factors would allow obtaining accurate cancer risk prediction models and providing personalized genetic counselling.
The BRCA genes are involved in the homologous recombination (HR) DNA repair pathway and, consequently, cells with deleterious mutations in these genes are highly dependent on other repair pathways. In particular, tumors with BRCA1 or BRCA2 mutations are selectively sensitive to the treatment with inhibitors of the protein PARP1 from the base excision repair (BER) pathway. This phenomenon is referred to as synthetic lethality and has positioned PARP1 inhibitors as promising drugs for the treatment of breast or ovarian cancers deficient in BRCA1 or BRCA2.
Bearing in mind these facts, our research group previously carried out a study that analysed genes involved in BER as candidate cancer risk modifiers in women carrying germline mutations in the BRCA genes. The polymorphisms identified with higher statistical evidence as risk modifiers were localized in glycosylase genes. The first objective of this thesis has been the characterization, by using functional studies, of the molecular basis through which the studied genetic variants, localized in regulatory regions of the NEIL2 and UNG genes, contribute to modify cancer risk.
NEIL2 SNP rs804271, linked to higher breast cancer risk in BRCA2 mutation carriers, is associated with NEIL2 overexpression and higher accumulation of oxidative damage in the telomeric DNA of women harbouring a BRCA2 mutation. On the other hand, UNG SNP rs34259, linked to a protective effect for ovarian cancer risk in BRCA2 mutation carriers, is associated with a lower UNG expression and lower uracil levels at telomeres in BRCA2 mutations carriers. These and other findings, reported in the present thesis, help to explain the association of these SNPs with cancer risk, highlighting the importance of genetic changes in glycosylase genes as modifiers of cancer susceptibility for BRCA genes mutation carriers.
Secondly, because of the essential role of the BER pathway in maintaining telomere integrity, we aimed to analyse the consequences of pharmacological inhibition of OGG1 glycosylase at the telomeres of tumoral cells as a possible therapeutic strategy. Our results show that, upon oxidative stress conditions, OGG1 inhibition blocks BER at telomeres. As a consequence, telomere instability, post-mitotic defects, and lower cell proliferation are generated. Therefore, these results show that OGG1 is necessary to preserve telomere homeostasis and present OGG1 inhibitors as a tool to induce oxidative DNA damage at telomeres, with potential implications in cancer and aging research.
Finally, we have studied the possible synthetic lethality relationship between OGG1 and BRCA1 on breast tumoral cells with silenced BRCA1, as well as the impact of the combined treatment of PARP1 and OGG1 inhibitors. The OGG1 inhibitor TH5487 decreases cell viability in a higher proportion when BRCA1 is silenced. Besides, TH5487 increases the therapeutic effect of the PARP1 inhibitor olaparib. These findings could lead to a new framework for the treatment of hereditary breast and ovarian cancer
