Germline Mutational Landscape and Novel Targetable <i>RAD51D</i> Variant in Chinese Patients With Ovarian Cancer.

Abstract

Genetic variants of ovarian cancer (OV) show ethnic differences, but data from the Chinese population are still insufficient. Here, we elucidate the inheritance landscape in Chinese patients with OV and examine the functional implications of a Chinese-enriched <i>RAD51D</i> variant. Between 2015 and 2018, 373 consecutive patients with OV were prospectively enrolled. Variants of <i>BRCA1/2</i>, other homologous recombination repair (HRR) genes, and DNA mismatch repair (MMR) genes were analyzed using next-generation sequencing. An enriched <i>RAD51D</i> variant was identified, and its functional effects were examined using Cell Counting Kit-8, colony formation, transwell migration, and drug sensitivity assays. Overall, 31.1% (116/373) of patients had at least one pathogenic or likely pathogenic germline variant. <i>BRCA1</i> and <i>BRCA2</i> accounted for 16.09% and 5.36%, respectively, with one patient having both variants. In addition, 32 (8.58%) patients carried other HRR gene variants, whereas three (0.8%) patients had MMR gene variants. The <i>RAD51D</i> variant ranked third (8/373, 2.1%), and its rate was much higher than that in other populations. Remarkably, all eight patients harbored the <i>RAD51D</i> K91fs variant (c.270_271dup, p.Lys91Ilefs*13) and demonstrated satisfactory platinum response and favorable prognosis. This variant confers enhanced sensitivity to poly (ADP-ribose) polymerase inhibitors in OV cells. However, the effects on platinum sensitivity were inconsistent across different cell lines. Against the background of the <i>TP53</i> variant, <i>RAD51D</i> K91fs variant showed increased sensitivity to cisplatin. Our study revealed the inheritance landscape of OV and identified an enriched <i>RAD51D</i> variant in Chinese patients with OV. This can serve as an important reference for OV management and a potential therapeutic target.