Whole exome sequencing of germline DNA from familial non-BRCA1/2 breast cancer cases with a homogeneous tumour profile

Chapter 5 Whole exome sequencing of germline DNA from familial non-BRCA1/2 breast cancer cases with a homogeneous tumour profile 110 Abstract Introduction A large proportion of familial breast cancer susceptibility is still unexplained. Inherited germline mutations in the high-risk BRCA1, BRCA2, and PALB2 genes account for approximately 10 to 20 percent of familial breast cancer risk. The failure to discover other high risk genes by means of linkage studies suggests a great degree of genetic heterogeneity underlying breast cancer susceptibility and that novel high-risk genes either do not exist or are rare and difficult to detect. In a previous study, we identified a small number of familial non-BRCA1/2 mutated (BRCAX) basal-like breast carcinomas with shared genomic features. These features include recurrent characteristic copy number aberrations and most notably, similar to the BRCA1-related tumours in this study, copy number neutral LOH of large overlapping genomic regions on chromosome 17. We hypothesized these BRCAX samples to constitute a genetically more homogeneous group as compared to unselected BRCAX samples. This homogeneity could be caused by pathogenic germline mutations in the same high or moderate-risk breast cancer gene, or alternatively, multiple mutated genes acting in the same pathway.