Unveiling mechanisms of tumor formation linked to BRCA2 mutation
Worldwide Cancer Research
Spanish National Research Council
Inactivating germline mutations affecting a single copy of BRCA2 are associated with an increased risk of breast and ovarian cancer. However, what drives tumorigenesis in carriers of heterozygous BRCA2 mutations remains elusive. Moreover, BRCA2 deficient breast tumors lack a clear pathological phenotype that distinguishes them from sporadic cancers so the identification of a molecular signature of tumor formation associated with BRCA2 deficiency remains a challenge. Over recent years, many mutational signatures have been generated corresponding to different types of tumors including BRCA1/2 associated breast cancer. However, a defective BRCA2 gives rise to at least five mutational signatures and although they have been associated with homologous recombination (HR) deficiency, not all HR deficient genes lead to the same outcome. Furthermore, BRCA1 and BRCA2-mutated tumors can be discriminated against using these mutational signatures suggesting that mechanisms specific to each gene might be acting as potential cancer drivers. This is perhaps not surprising given the number of functions the two proteins exert in cells. As these different functions are mapped to distinct regions in the protein, we argue that different mutations in a single gene could reveal different mechanisms of tumor formation. Thus, by focusing on BRCA2-mutated tumors bearing a common pathogenic mutation we may unveil new mechanisms of tumor formation that would otherwise remain “hidden” in the population of BRCA2-mutated tumors. In addition, by recreating these mutations in relevant breast epithelial cells in heterozygosis we will be able to confirm which of the deregulated pathways observed in tumors are specifically due to BRCA2 mutation. Our preliminary results reveal a substitution signature prevalent in tumors bearing a specific pathogenic mutation and a deregulated pathway that was confirmed in our heterozygous cell system expressing the same mutation thus supporting this hypothesis. If confirmed, this project will have important clinical implications for prevention and treatment.
2.1 Biological and endogenous factors