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- Breast cancer is the most common cancer in women worldwide. Familial breast cancer (FBC) is expected to account for up to 15% of breast cancers. Although recent breakthroughs have resulted in the identification of distinct new groups of genetically inherent breast cancer genes, about 64% of the genetic predisposition to FBC remains unexplained. Therefore, new approaches are required to identify remaining genetic factors underlying FBC susceptibility. This is crucial because the elucidation of inherent cancer defects offers the ability to counsel and monitor patients. Importantly, it also provides firm ground for therapeutically targeting particular cancer pathways for example through Poly ADP-ribose polymerase inhibitors (PARPi) that exploit synthetic lethality with particular DNA repair deficiencies. To advance the field, my host lab has performed High-Throughput phenotypic screen, based on gene variants recognized in a FBC cohort of 135 early-onset (age <35 years) breast cancer patients through whole exome sequencing. The 270 new genes with potential disease association were enrolled in screens, focusing on genome maintenance and PARPi sensitivity. These unique preliminary data form the basis for my project. I hypothesize that by performing following specific analyses I will be able to elucidate new FBC predisposition genes: •Ranking of screen hits by performing FBC-associated variant analysis in an international and Danish FBC cohort. •Elucidating molecular function of novel FBC predisposition genes in genome maintenance. •Unraveling the molecular network of candidate proteins by unbiased Mass-spectrometry as well as follow-up analysis of interactors. I anticipate that my work will provide novel FBC predisposition genes, which will markedly contribute to clinical risk assessment tools (such as targeted sequencing) by ensuring identification of individuals at elevated risk who benefit from advances in surveillance and targeted interventions.