Mechanisms underlying homologous recombination DNA repair deficiency in ovarian cancer and association with treatment response

Abstract

Homologous recombination (HR) DNA repair deficiency (HRD) is a defining feature of high-grade serous ovarian carcinoma (HGSC) and canonically results from faults in BRCA1/2, which are associated with genomic rearrangements known as a genomic scar. A major advance in ovarian cancer treatment is the use of poly (ADP-ribose) polymerase inhibitors (PARPi), which leverage synthetic lethality with HRD. However, efforts to identify patients with HRD for treatment with PARPi have only been partly successful and responses can be variable. The aim of this project was therefore to determine the relationship between canonical and novel causes of HRD in altering genomic states and clinical outcomes in patients with epithelial ovarian cancer. Cases from the INOVATe cohort were tested with a genomic scar assay, next-generation sequencing and RAD51 foci staining. Treatment and survival outcomes were analysed. While most cases with evidence of HRD on a genomic scar assay were associated with mutations or methylation of a gene with a known role in HRD, some cases appeared HR-deficient without an apparent lesion. Variants were identified which may contribute to HRD by destabilizing r-loop processing. Functional measurement suggested that many cases had low levels of HR repair, even in the absence of a pathway fault. Genomic scar scores and canonical gene variants were associated with improved survival. A classifier based on genomic features aligned to chemotherapy response identified three clusters with differing associations of genomic instability, BRCA-like features and treatment outcomes. In conclusion, variants in BRCA1/2 appear to drive a phenotype which includes, but is not limited to, HRD. Genotypic and phenotypic correlates of HRD only partially account for treatment responses. Faults in r-loop processing appear to drive some HRD and clinical responses. BRCA-independent HRD in HGSC is not necessarily associated with outcomes analogous to BRCA1/2 loss.