Objective: To investigate the mutations of BRCA genes in sporadic high grade serous ovarian cancer (HGSOC) and study its clinical significance. Methods: Sixty-eight patients between January 2015 and January 2016 from the Affiliated Cancer Hospital of Zhengzhou University were collected who were based on pathological diagnosis of ovarian cancer and had no reported family history, and all patients firstly hospitalized were untreated in other hospitals before. (1) The BRCA genes were detected by next-generation sequencing (NGS) method. (2) The serum tumor markers included carcinoembryonic antigen (CEA), CA(125), CA(199), and human epididymis protein 4 (HE4) were detected by the chemiluminescence methods, and their correlation was analyzed by Pearson linear correlation. Descriptive statistics and comparisons were performed using two-tailed t-tests, Pearson's chi square test, Fisher's exact tests or logistic regression analysis as appropriate to research the clinicopathologic features associated with BRCA mutations, including age, International Federation of Gynecology and Obstetrics (FIGO) stage, platinum-based chemotherapy sensitivity, distant metastases, serum tumor markers (STM) . Results: (1) Fifteen cases (22%, 15/68) BRCA mutations were identified (BRCA1: 11 cases; BRCA2: 4 cases), and four novel mutations were observed. (2) The levels of CEA, CA(199), and HE4 were lower in BRCA mutations compared to that in control group, while no significant differences were found (P>0.05), but the level of CA(125) was much higher in BRCA mutation group than that in controls (t=-3.536, P=0.003). Further linear regression analysis found that there was a significant linear correlation between CA(125) and HE4 group (r=0.494, P<0.01), and the same correlation as CEA and CA(199) group (r=0.897, P<0.01). (3) Single factor analysis showed that no significant differences were observed in onset age, FIGO stage, distant metastasis, and STM between BRCA(+) and BRCA(-) group (P>0.05), while significant differences were found in CA(125) and sensitivity to platinum-based chemotherapy between the patients with BRCA mutation and wild type (P<0.05). The multiple factors analysis showed that the high level of CA(125) was a independent risk factor of BRCA mutations in sporadic HGSOC (P=0.007). Conclusion: The combination of CA(125) with BRCA have great clinical significance, the mutation of BRCA gene could guild the clinical chemotherapy regiments.
目的：探讨散发性高级别卵巢浆液性癌（HGSOC）的BRCA基因突变情况及其临床意义。 方法：收集2015年1月-2016年1月郑州大学附属肿瘤医院收治的病理诊断为HGSOC且患者家族中无乳腺癌或卵巢上皮性癌病史、患者本人无乳腺癌病史者（即散发性HGSOC患者）共68例纳入本研究，所有患者入院前未予任何治疗。（1）采用第2代基因测序（NGS）技术检测散发性HGSOC患者的BRCA基因突变情况；（2）采用化学发光法检测散发性HGSOC患者血清肿瘤标志物包括癌胚抗原（CEA）、CA(125)、CA(199)、人附睾蛋白4（HE4）的表达水平，并采用Pearson线性相关分析法对散发性HGSOC患者不同血清肿瘤标志物的水平进行相关性分析；（3）对影响散发性HGSOC患者BRCA基因突变的因素（包括年龄、手术病理分期、远处转移、铂类药物敏感性以及血清CEA、CA(125)、CA(199)、HE4水平等）进行分析，单因素分析采用χ(2)检验、Fisher确切概率法，多因素分析采用logistic回归法。 结果： （1）68例散发性HGSOC患者中，15例患者存在BRCA基因突变，BRCA基因突变率为22%（15/68），其中BRCA1基因突变率为16%（11/68）、BRCA2基因突变率为6%（4/68）；且15例BRCA基因突变患者中4例为新发突变。（2）BRCA基因突变型患者的血清CEA、CA(199)、HE4水平均低于BRCA基因野生型（即BRCA基因未突变）患者，但两者分别比较，差异均无统计学意义（P>0.05）；而BRCA基因突变型患者的血清CA(125)水平明显高于BRCA基因野生型患者（t=-3.536，P=0.003）。进一步行Pearson线性相关分析显示，CEA与CA(199)（r=0.897，P<0.01）、CA(125)与HE4（r=0.494，P<0.01）之间均呈明显正相关。（3）单因素分析显示，BRCA基因突变与散发性患者的年龄、手术病理分期、远处转移以及血清CEA、CA(199)、HE4水平均无关（P>0.05），而与血清CA(125)水平、铂类药物敏感性均明显相关（P<0.05）；多因素分析显示，血清CA(125)高水平是影响散发性HGSOC患者BRCA基因突变的独立危险因素（P=0.007）。 结论：血清CA(125)高水平能够提示散发性HGSOC患者BRCA基因突变情况；BRCA基因突变型患者对以铂类药物为基础的联合化疗方案更加敏感，能够指导临床化疗用药。.
Keywords: Antineoplastic combined chemotherapy protocols; CA-125 antigen; Cystadenocarcinoma, serous; Genes, BRCA1; Genes, BRCA2; Mutation; Ovarian neoplasms.