Mutations in BRCA1, BRCA2 and several other susceptibility genes only account for 25% of familial breast cancer. Towards understanding the genetics of the other 75% of familial breast cancer patients in Ireland, we performed targeted DNA sequencing of 312 cancer associated genes in 104 Irish women with hereditary, non-BRCA1/2 breast cancer (Aloraifi et al, 2015 and Figure 1). This identified many mutations in the exons of genes encoding known oncogenes, including ERBB2, AURKB and ZNF217, as well as candidate tumour suppressor genes. This grant project will test the hypothesis that some of these mutations could be pathogenic by exploring both their functional and clinical relevance.
The project design is based on our ‘proof of principal’ experiment in which we used CRISPR DNA editing to show that a germline mutation we identified in the ERBB2 oncogene leads to its constitutive activation in a cell line model (Figure 2). This project aims to expand on this discovery to use CRISPR to develop isogenic breast cancer cell line models to characterise several additional potentially causative mutations, which we hypothesise could account for up to 15% of all non-BRCA1/2 familial breast cancer cases in our patient cohort. We will use these cell line models to evaluate both the in vitro and in vivo functional consequences of key germline mutations, including monitoring their respective responsiveness to established ‘biologic’ therapies. We will also explore the prevalence of these selected mutations on independent Irish national and international patient cohorts to more fully evaluate the potential impact of our work.
This integrative approach will involve an international team with expertises in genetics, cancer biology, biostatistics, bioinformatics and CRISPR engineering, which together will work towards expanding the use of already established biological therapies in the targeted treatment of familial breast cancer.
