Mutational landscape and risk estimates of DDR genes in Chinese ovarian cancer patients.

BACKGROUND: Pathogenic/likely pathogenic variants (P/LPVs) in DNA damage response (DDR) genes are known ovarian cancer (OC) risk factors, but gene-specific risk estimates in Han Chinese remain unclear. OBJECTIVE: To accurately assess the risk associated with DDR genes in the Han Chinese population to facilitate personalized risk management and enhance clinical decision-making. METHODS: We performed next-generation sequencing of 45 DDR genes in 666 OC patients from Henan, China. Associations between P/LPVs and clinical features were assessed using chi-squared tests. Variant frequencies were compared with population controls (gnomAD and ChinaMAP databases) to estimate gene-specific odds ratios (ORs) using Fisher’s test. RESULTS: In Henan Ovarian Cancer patients, the median disease onset age was 53 years (range: 24–81), with 7.7% diagnosed before 40. Most patients had advanced disease (56.5% Stage III, 18.9% Stage IV), and 75.8% had high-grade serous carcinoma (HGSC). P/LPVs in BRCA1/2 were significantly associated with the HGSC subtype and a positive family history (p < 0.001 for both). Beyond BRCA1 (OR = 125.5/146.1) and BRCA2 (OR = 17.9/20.2), significantly elevated ovarian cancer risks were observed for RAD51D, RAD51C, and MSH2 (OR: 10.1–35.4, all p < 0.05). CONCLUSIONS: This study provides the first gene-specific ovarian cancer risk estimates for DDR genes in Han Chinese, expanding the high-risk gene spectrum. By defining population-specific risk magnitudes, our findings provide a framework for clinical risk stratification, and underscore the need to tailor screening and prevention strategies to China’s distinct genetic landscape.