The molecular landscape of homologous recombination deficient, end-stage, high grade serous ovarian cancer

High grade serous cancer (HGSC) is frequently characterizsed by homologous recombination (HR) DNA repair deficiency, and while most such tumours are sensitive to initial treatment, acquired resistance is common. We undertook a multi-omics approach to interrogating mechanisms of resistance, using multiple autopsy samples collected from 15 women with HR-deficient HGSC. We observed frequent reversion mutations, resistance mechanisms restoring HR by other means, a high frequency of whole-genome duplication (WGD) suggestive of an evolutionary advantage, and global changes in immune composition with evidence of immune escape. Collectively these findings have implications for therapeutic intervention for HR-deficient HGSC.