Introduction Gene mutations in ovarian cancer demonstrate ethnic differences, and data among Chinese is still insufficient. Here, we elucidated the inherited landscape of Chinese ovarian cancer patients, and further investigated the functional implication of a Chinese-specific enriched RAD51D mutation.

Methods Between 2015 and 2018, 373 consecutive ovarian cancer patients were prospectively enrolled. Mutations of BRCA1/2, other HRR genes and MMR genes were analyzed by next-generation sequencing. A specific pathogenic RAD51D mutation was identified, and its functional implications were investigated by CCK-8 and Colony formation, transwell migration and drug sensitivity assays.

Results Overall, 31.1% (116/373) of patients harbored at least one pathogenic or likely pathogenic germline variant. BRCA1 and BRCA2 accounted for 16.09% and 5.36% respectively, with one patient harboring both mutations. Besides, 32 (8.58%) patients carried other HRR gene mutations, while 3 (0.8%) patients had MMR gene mutations. RAD51D mutation ranked third (8/373, 2.1%) and the rate was much higher compared with other population. Remarkably, all eight patients had a K91fs variant, and presented with satisfactory platinum response and favorable prognoses. This variant conferred enhanced sensitivity to PARP inhibitors in ovarian cancer cells. However, effects on platinum sensitivity were inconsistent among different cell lines. Only under the background of TP53 mutation, RAD51D K91fs mutation could increase the sensitivity to cisplatin.

Conclusion/Implications Our study revealed the inherited landscape of ovarian cancer, and identified a specific enriched RAD51D mutation of Chinese ovarian cancer patients. It can serve as an important reference for ovarian cancer management and provide a potential treatment target.