A unique long-read genome sequencing approach to identify structural variants predisposing to hereditary breast cancer
Final Report Abstract
Breast cancer is the most common cancer among women, with genetic predisposition playing a significant role. While variants in BRCA1 and BRCA2 are the most significant genetic factors, responsible for about 25% of hereditary breast and ovarian cancer (HBOC), additional risk genes have also been identified. However, the heritability and underlying genetic factors remain unexplained in the majority of HBOC patients. Disease-causing BRCA1/BRCA2 variants can confer a high lifetime risk of breast cancer and are associated with other cancers as well. Breast cancer can also be part of cancer predisposition syndromes with a diverse tumor spectrum. Identifying predisposing gene variants is crucial for tailoring treatment and preventive strategies. Recent research to uncover predisposing genetic factors has mainly relied on shortread exome sequencing, but has only explained a small percentage of HBOC inheritance. We hypothesized that intronic or intergenic variants disrupting regulatory elements as well as structural aberrations in known HBOC-associated and hitherto unknown genes may contribute to familial tumor predisposition. To address this, we used an innovative synergistic approach of combining long-read (PacBio) and short-read (Illumina) whole-genome sequencing to identify novel mutational mechanisms in known HBOC-associated genes as well as mutations in novel genes predisposing to breast cancer. In our project, we have further established an automated pipeline for comprehensive processing and analysis of PacBio long-read sequencing data. We yet identified several novel cancer predisposing candidate genes, which can now subsequently be tested in larger patient cohorts. Our results further provide the basis for extensive functional studies to investigate in detail the role of the identified genes in breast cancer development.
