Abstract
Patients with high-grade serous ovarian carcinoma (HGSOC) with BRCA1/2 mutations show homologous recombination (HR) deficiency (HRD) and poly (ADP-ribose) polymerase inhibitors (PARPi) sensitivity. Notably, HRD and PARPi response can occur without BRCA mutations, suggesting that other factors are involved. Loss of coiled-coil domain containing 6 (CCDC6) function can lead to HRD and PARPi sensitivity in HGSOC cells, making CCDC6 a potential therapeutic target and biomarker. Three CCDC6 missense mutations in HGSOC prompted an investigation into their impact on HRD. Analyzing CCDC6 expression, localization, and HRD data in the MITO16A trial aims to clarify the CCDC6-HRD relationship in a large cohort. The biochemical and morphologic effects of CCDC6 mutants on the native protein were examined using pull-down assays and immunofluorescence. HR-reporter and cell viability assays determined the impact of these mutants on HRD and PARPi sensitivity. The CCDC6 histochemical score and intracellular localization were assessed in MITO16A samples after immunostaining and digitalization. CCDC6-mutated isoforms act as dominant-negative, preventing native CCDC6 nuclear translocation, disrupting RAD51 foci and HR repair, and increasing PARPi sensitivity. In the MITO16A patient sample set, 66 of 185 (35%) showed barely detectable CCDC6 or nuclear exclusion ("CCDC6-inactive"). CCDC6 impairment in these "CCDC6-inactive" samples was associated with HRD in 75% (30/40) of suitable samples analyzed by the RAD51 test and in 52% (34/65) of suitable samples analyzed by genomic HRD testing, even in the presence of wild-type (WT) BRCA1/BRCA2 genes. The association between CCDC6 inactivity and HRD, both at the genomic and functional levels, occurred even in the presence of WT BRCA1/BRCA2 genes, suggesting that CCDC6 may play a crucial role in DNA repair pathways independent of these well-known genes. Significance: In ovarian cancer, inactivation of the CCDC6 protein signals a defect in DNA repair, known as HRD. This finding might expand the pool of patients, including those who are BRCA WT, who can receive PARP inhibitors, significantly broadening access to this targeted, life-extending therapy.