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Abstract：
OBJECTIVE: To define genetic profiling of homologous recombination (HR) deficiency in Chinese ovarian cancer patients.
METHODS: we have applied next-generation sequencing to detect deleterious mutations through all exons in 31 core HR genes. Paired whole blood and frozen tumor samples from 50 Chinese women diagnosed with epithelial ovarian carcinomas were tested to identify both germline and somatic variants.
RESULTS: Deleterious germline HR-mutations were identified in 36% of the ovarian cancer patients. Another 5 patients had only somatic mutations. BRCA2 was most frequently mutated. Three out of the 5 somatic mutations were in RAD genes and a wider distribution of other HR genes was involved in non-serous carcinomas. BRCA1/2-mutation carriers had favorable platinum sensitivity (relative risk, 1.57, p<0.05), resulting in a 100% remission probability and survival rate. In contrast, mutations in other HR genes predicted poor prognosis. However, multivariate analysis demonstrated that platinum sensitivity and optimal cytoreduction were the independent impact factors influencing survival (hazards ratio, 0.053) and relapse (hazards ratio, 0.247), respectively.
CONCLUSIONS: our results suggest that a more comprehensive profiling of HR defect than merely BRCA1/2 could help elucidate tumor heterogeneity and lead to better stratification of ovarian cancer patients for individualized clinical management.
METHODS: we have applied next-generation sequencing to detect deleterious mutations through all exons in 31 core HR genes. Paired whole blood and frozen tumor samples from 50 Chinese women diagnosed with epithelial ovarian carcinomas were tested to identify both germline and somatic variants.
RESULTS: Deleterious germline HR-mutations were identified in 36% of the ovarian cancer patients. Another 5 patients had only somatic mutations. BRCA2 was most frequently mutated. Three out of the 5 somatic mutations were in RAD genes and a wider distribution of other HR genes was involved in non-serous carcinomas. BRCA1/2-mutation carriers had favorable platinum sensitivity (relative risk, 1.57, p<0.05), resulting in a 100% remission probability and survival rate. In contrast, mutations in other HR genes predicted poor prognosis. However, multivariate analysis demonstrated that platinum sensitivity and optimal cytoreduction were the independent impact factors influencing survival (hazards ratio, 0.053) and relapse (hazards ratio, 0.247), respectively.
CONCLUSIONS: our results suggest that a more comprehensive profiling of HR defect than merely BRCA1/2 could help elucidate tumor heterogeneity and lead to better stratification of ovarian cancer patients for individualized clinical management.
摘要：
目的：定义中国卵巢癌患者同源重组（HR）缺陷的遗传图谱。
方法：我们已经应用下一代测序来检测31个核心HR基因中所有外显子的有害突变。对来自50名诊断为上皮性卵巢癌的中国女性的配对全血和冷冻肿瘤样品进行了测试，以鉴定种系和体细胞变异。
结果：在36％的卵巢癌患者中发现了有害的种系HR突变。另外5名患者只有体细胞突变。BRCA2是最常见的突变。5个体细胞突变中有3个在RAD基因中，其他HR基因的更广泛分布与非浆液性癌有关。BRCA1/2突变携带者具有良好的铂敏感性(相对风险，1.57，p<0.05），导致100%的缓解概率和生存率。相比之下,其他HR基因突变预测预后不良.然而,多变量分析表明，铂敏感性和最佳细胞减少是影响生存率的独立影响因素(危险比，0.053)和复发(危险比，0.247)，分别。
结论：我们的结果表明，比仅仅BRCA1/2更全面地分析HR缺陷可能有助于阐明肿瘤异质性，并导致卵巢癌患者更好地分层以进行个体化临床治疗。
方法：我们已经应用下一代测序来检测31个核心HR基因中所有外显子的有害突变。对来自50名诊断为上皮性卵巢癌的中国女性的配对全血和冷冻肿瘤样品进行了测试，以鉴定种系和体细胞变异。
结果：在36％的卵巢癌患者中发现了有害的种系HR突变。另外5名患者只有体细胞突变。BRCA2是最常见的突变。5个体细胞突变中有3个在RAD基因中，其他HR基因的更广泛分布与非浆液性癌有关。BRCA1/2突变携带者具有良好的铂敏感性(相对风险，1.57，p<0.05），导致100%的缓解概率和生存率。相比之下,其他HR基因突变预测预后不良.然而,多变量分析表明，铂敏感性和最佳细胞减少是影响生存率的独立影响因素(危险比，0.053)和复发(危险比，0.247)，分别。
结论：我们的结果表明，比仅仅BRCA1/2更全面地分析HR缺陷可能有助于阐明肿瘤异质性，并导致卵巢癌患者更好地分层以进行个体化临床治疗。
