国人卵巢癌DNA损伤修复基因突变图谱分析

  目的  同源重组修复（homologous recombination repair，HRR）基因BRCA1/2在卵巢癌的发生发展中起到了重要作用，相关研究比较深入，而对于其他DNA损伤修复（DNA-damage repair，DDR）基因突变在中国卵巢癌人群中的分布及其与患者临床特征之间的关系仍缺乏详细的探讨。  方法  本研究纳入2019年6月至2020年6月在天津医科大学肿瘤医院接受手术治疗的卵巢癌患者122例，收集其外周血样本和67例对应肿瘤组织标本，利用二代测序技术检测19个DDR基因的变异情况、分布特点和临床病理相关性。  结果  胚系DDR基因突变主要集中在HRR基因，占80.37%，致病性和可能致病性突变全部集中在HRR基因。携带胚系HRR（germline HRR，gHRR）突变的患者较BRCA突变的更多（31.15% vs. 23.77%），且呈现家族聚集现象，病理类型以浆液性腺癌为主，并与铂类药物敏感性相关。肿瘤组织层面DDR基因突变中HRR基因突变率仅次于TP53，占39.39%。检出肿瘤组织HRR（tumor HRR，tHRR）突变的患者较gHRR突变的患者多5.97%。tHRR突变患者对铂类药物治疗敏感，且复发风险更低。  结论  揭示中国卵巢癌DDR基因突变特征，提示基于二代测序的DDR多基因检测可指导卵巢癌患者的精准诊疗。 

Analysis of mutational spectrum of DNA-damage repair genes in Chinese patients with ovarian cancer

  Objective  Homologous recombination repair (HRR) genes play an important role in the carcinogenesis of ovarian cancer (OC). At present, the mutations in breast cancer 1 (BRCA1) and breast cancer 2 (BRCA2) genes are well-characterized in OC. However, the characterization of DNA-damage repair (DDR) genes in Chinese patients with OC, as well as the relationship between HRR mutations and clinical features remain unclear.   Methods  From June 2019 to June 2020, 122 peripheral blood samples and 67 tumor tissue samples of OC patients were collected from Tianjin Medical University Cancer Institute & Hospital, respectively. All methods were performed under the permission of the hospital’s ethics committee. Mutations in 19 DDR-related genes, including HRR and mismatch repair (MMR) genes, were detected via next-generation sequencing.   Results  Next generation sequencing results revealed that germline mutations were mainly concentrated in HRR genes (80.37%). The number of patients with germline HRR (gHRR) mutations was more than the number of patients with BRCA mutations (31.15% vs. 23.77%). Patients with gHRR mutations showed familial aggregation, serous adenocarcinoma, and platinum sensitivity. In tumor tissue, the most common somatic mutation is in the tumor protein p53 (TP53) gene, followed by mutations in HRR genes (39.39%). The number of patients with tumor HRR (tHRR) mutations was 5.97% greater than the number of patients with gHRR mutations. Patients with tHRR mutations not only shared the same characteristics as patients with gHRR mutations but also had a lower risk of recurrence.   Conclusions  This study revealed characteristics of DDR mutations in Chinese OC patients and these findings suggest that the detection of mutations in DDR genes can guide the diagnosis and treatment of OC.