Abstract：
OBJECTIVE: 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 RAD51D variant.
METHODS: Between 2015 and 2018, 373 consecutive patients with OV were prospectively enrolled. Variants of BRCA1/2, other homologous recombination repair (HRR) genes, and DNA mismatch repair (MMR) genes were analyzed using next-generation sequencing. An enriched RAD51D variant was identified, and its functional effects were examined using Cell Counting Kit-8, colony formation, transwell migration, and drug sensitivity assays.
RESULTS: Overall, 31.1% (116/373) of patients had at least one pathogenic or likely pathogenic germline variant. BRCA1 and BRCA2 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 RAD51D variant ranked third (8/373, 2.1%), and its rate was much higher than that in other populations. Remarkably, all eight patients harbored the RAD51D 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 TP53 variant, RAD51D K91fs variant showed increased sensitivity to cisplatin.
CONCLUSIONS: Our study revealed the inheritance landscape of OV and identified an enriched RAD51D variant in Chinese patients with OV. This can serve as an important reference for OV management and a potential therapeutic target.
METHODS: Between 2015 and 2018, 373 consecutive patients with OV were prospectively enrolled. Variants of BRCA1/2, other homologous recombination repair (HRR) genes, and DNA mismatch repair (MMR) genes were analyzed using next-generation sequencing. An enriched RAD51D variant was identified, and its functional effects were examined using Cell Counting Kit-8, colony formation, transwell migration, and drug sensitivity assays.
RESULTS: Overall, 31.1% (116/373) of patients had at least one pathogenic or likely pathogenic germline variant. BRCA1 and BRCA2 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 RAD51D variant ranked third (8/373, 2.1%), and its rate was much higher than that in other populations. Remarkably, all eight patients harbored the RAD51D 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 TP53 variant, RAD51D K91fs variant showed increased sensitivity to cisplatin.
CONCLUSIONS: Our study revealed the inheritance landscape of OV and identified an enriched RAD51D variant in Chinese patients with OV. This can serve as an important reference for OV management and a potential therapeutic target.
摘要：
目的：卵巢癌（OV）的遗传变异表现出种族差异，但是中国人口的数据仍然不足。这里,我们阐明了中国OV患者的遗传景观，并研究了富含中国人的RAD51D变体的功能含义。
方法：在2015年至2018年之间，前瞻性招募了373例OV患者。BRCA1/2，其他同源重组修复（HRR）基因的变体，和DNA错配修复（MMR）基因使用下一代测序进行分析。鉴定了一个富集的RAD51D变体，并使用细胞计数试剂盒-8，集落形成，Transwell迁移,和药物敏感性测定。
结果：总体而言，31.1％（116/373）的患者至少有一种致病性或可能致病性种系变异。BRCA1和BRCA2分别占16.09%和5.36%,分别,一名患者有两种变体。此外,32例（8.58%）患者携带其他HRR基因变异，而3例(0.8%)患者有MMR基因变异.RAD51D变体排名第三（8/373，2.1％），其发病率远高于其他人群。值得注意的是,所有八名患者都携带RAD51DK91fs变体(c.270_271dup，p.Lys91Ilefs*13）并显示出令人满意的铂类反应和良好的预后。该变体赋予OV细胞中对聚(ADP-核糖)聚合酶抑制剂的增强的敏感性。然而,不同细胞系对铂敏感性的影响不一致.在TP53变体的背景下，RAD51DK91fs变体显示对顺铂的敏感性增加。
结论：我们的研究揭示了OV的遗传景观，并在中国OV患者中确定了丰富的RAD51D变异。这可以作为OV管理的重要参考和潜在的治疗靶标。
方法：在2015年至2018年之间，前瞻性招募了373例OV患者。BRCA1/2，其他同源重组修复（HRR）基因的变体，和DNA错配修复（MMR）基因使用下一代测序进行分析。鉴定了一个富集的RAD51D变体，并使用细胞计数试剂盒-8，集落形成，Transwell迁移,和药物敏感性测定。
结果：总体而言，31.1％（116/373）的患者至少有一种致病性或可能致病性种系变异。BRCA1和BRCA2分别占16.09%和5.36%,分别,一名患者有两种变体。此外,32例（8.58%）患者携带其他HRR基因变异，而3例(0.8%)患者有MMR基因变异.RAD51D变体排名第三（8/373，2.1％），其发病率远高于其他人群。值得注意的是,所有八名患者都携带RAD51DK91fs变体(c.270_271dup，p.Lys91Ilefs*13）并显示出令人满意的铂类反应和良好的预后。该变体赋予OV细胞中对聚(ADP-核糖)聚合酶抑制剂的增强的敏感性。然而,不同细胞系对铂敏感性的影响不一致.在TP53变体的背景下，RAD51DK91fs变体显示对顺铂的敏感性增加。
结论：我们的研究揭示了OV的遗传景观，并在中国OV患者中确定了丰富的RAD51D变异。这可以作为OV管理的重要参考和潜在的治疗靶标。
