Genomic susceptibility to invasive lobular breast cancer

Invasive lobular breast cancer is a specific histological type of breast cancer that makes up about 10% of all invasive breast cancer diagnoses. It has been known for some time that relatives of lobular breast cancer cases have an increased risk of lobular breast cancer (familial relative risk 4.51 95% CI 2.79-6.89) strongly suggesting that lobular breast cancer has a heritable component that may represent a genetically homogeneous form of breast cancer compared to other subtypes. We have applied whole genome massively parallel sequencing to highly-selected multiple-case lobular breast cancer families from international resources. Early analyses of 120 whole genome sequences has been focused on the coding and flanking intronic regions of recognised genes. We have identified a very small number of families (n = 4) that carry pathogenic genetic variants in genes already known to be associated with breast cancer predisposition (BRCA1 and BRCA2). No families in this study have been found to carry pathogenic variants in CDH1, a gene know to be associated with susceptibility to hereditary diffuse gastric cancer and invasive lobular breast cancer. This project will conduct work to further consider large genomic structural variants, including copy number variants, using the whole genome data from participating families. Further work will involve expanding the analysis to population-based samples of breast cancer families to validate findings and estimate the disease penetrance of structural variants. The project will involve laboratory based work applying state-of-the-art molecular genetic analyses including massively parallel sequencing and apply a number of bioinformatics approaches to data analyses. Success of our project will provide the evidence base from which clinical cancer genetics services can improve personalized clinical management for women with invasive lobular breast cancer.