A comprehensive genomic framework for identifying genes predisposing to homologous recombination repair deficient breast cancer

Background Patients with clinical characteristics of increased cancer susceptibility without an identified genetic lesion are regularly seen in clinics. Case-control studies and matched normal/tumour sequencing have advanced the discovery of Cancer Susceptibility Genes (CSGs), with limitations when used independently. We reasoned that combining these strategies alongside mutational signatures and clinical data could improve CSGs identification. Methods Using breast cancer exome data from The Cancer Genome Atlas (TCGA-BRCA), we developed a genomic framework that evaluates exome-wide associations of Germline Pathogenic Variants (GPVs) with somatic second hits, within the context of the Homologous Recombination Repair Deficiency (HRD) mutational signature 3 (Sig3). This is complemented by clinico-genomic analysis evaluating clinical and biological plausibility. Results Our framework confirmed significant associations with Sig3 of BRCA1/2 GPVs with second hits, validating its performance. THBS4 also reached significance but co-occurred with other HRD-related events. Borderline significance was observed for KIF13B and TESPA1. The clinico-genomics approach further identified KIF13B and TESPA1, as well as RAD51B and other Fanconi Anemia pathway-related genes, which deserve further validation. Conclusions Our framework strengthens identification of candidate HRD-related breast CSGs through combined statistical and clinico-genomics analyses. It is adaptable to other mutational signatures/cancer types and will benefit from larger and well-annotated datasets.