Comprehensive Germline Profiling of High-Grade Serous Ovarian Cancer Using Whole-Exome Sequencing

While ovarian cancer screening is not recommended in the general population, attention has shifted to screening women with elevated hereditary risks. Although germline BRCA 1/2 pathogenic variants account for 40% of inherited ovarian cancer risk and family history (FH) remains important, known germline variants alone do not fully explain familial ovarian cancer risk. Whole-exome sequencing (WES) was performed on blood samples taken from 231 individuals, including 39 patients with high-grade serous ovarian cancer (HGSOC) and 192 healthy controls (HCs) stratified by FH. We analyzed pathogenic or likely pathogenic (P/LP) germline variants in cancer-related genes and assessed their association with family cancer history. Additionally, we performed somatic variant comparisons using 1:4 propensity score matching and analyzed clonal hematopoiesis of indeterminate potential (CHIP)-related somatic variants. P/LP germline variants were detected in 56.4% of HGSOC patients, 49.4% of controls with FH, and 33.3% without. The HGSOC group and controls with FH exhibited similar P/LP germline mutation patterns in ovarian cancer-related genes. From CHIP analysis, somatic CHIP mutations were detected in 6.3% of the HGSOC group and 8.5% in HCs. Our findings demonstrate genomic overlap between ovarian cancer patients and FH-positive individuals. Therefore, germline variant screening could be considered to facilitate early diagnosis.