Somatic panel testing reveals no common alternative oncogenic driver in BRCA1/2-mutant high-grade serous ovarian cancer with discordant low genomic instability score

High-grade serous ovarian cancer (HGSOC) is the commonest and most lethal subtype of ovarian cancer, accounting for approximately 70% of cases and associated with a poor 10-year survival of 30%–40%.1 Around 40% of all HGSOCs exhibit homologous recombination deficiency (HRD), most commonly due to loss of BRCA1/2 function.2 BRCA1 and BRCA2 are key mediators of the homologous recombination (HR), the high-fidelity pathway for repairing DNA double-strand breaks. Biallelic loss forces reliance on more error-prone pathways, notably alternative end joining (e.g., microhomology-mediated) and single-strand annealing, as well as classical non-homologous end joining. This produces large-scale genomic rearrangements, loss of heterozygosity (LOH) and characteristic mutational signatures that accumulate as a measurable, persistent pattern of genome-wide instability, often termed a ‘genomic scar’.3 Tumours with a BRCA1/2 pathogenic variant typically show marked genomic instability and respond well to platinum-based chemotherapy and poly(ADP-ribose) polymerase (PARP) inhibitors.4…