RAS相关区域家族1A基因甲基化对肝细胞癌患者术后预后的预测价值

Prognostic value of RAS association domain family 1A gene methylation in patients with hepatocellular carcinoma after surgery

目的 探讨RAS相关区域家族1A基因（RASSF1A）甲基化对预测行肝细胞癌手术切除术后患者预后的价值.方法 纳入260例行手术切除的肝细胞癌患者,留取其肝细胞癌组织和距病变外缘2 cm处的癌旁组织,并收集其临床病理资料.采用甲基化特异性PCR方法检测肝细胞癌组织和配对的癌旁组织中RASSF1A的甲基化状态.采用卡方检验分析RASSF1A甲基化的表达率及其与临床病理特征的关系.采用Log-rank检验分析RASSF1A甲基化与总生存率的关系.采用单因素和多因素Cox回归分析确定肝细胞癌预后的影响因素.结果 260份肝细胞癌组织和配对的癌旁组织中,214份（82.3％）的肝细胞癌组织中存在RASSF1A基因启动子区异常甲基化,配对的癌旁组织中有101份（38.8％）发生甲基化,差异有统计学意义（x2=102.824,P＜0.01）.RASSF1A甲基化与肝细胞癌患者的年龄、性别、是否肝硬化、AFP水平、肿瘤最大径、巴塞罗那临床肝癌（BCLC）分期、是否HBV感染、是否吸烟、是否饮酒之间均无相关性（P均＞0.05）.RASSF1A甲基化阴性患者的5年生存率为93％,RASSF1A甲基化阳性患者的为51％,两者的总体生存率差异有统计学意义（x2=26.556,P＜0.01）.单因素和多因素Cox回归分析发现,肝硬化、BCLC分期和RASSF1A甲基化是肝细胞癌患者术后死亡的主要影响因素（Wald值分别为16.767,8.791,16.286;P均＜0.01）.结论 RASSF1A甲基化不仅是肝细胞癌患者行手术切除术后生存率的预测因子之一,而且也是肝细胞癌的独立预后因素.

Objective To evaluate the prognostic value of RAS association domain family 1A gene （RASSF1A） methylation in patients after hepatocellular carcinoma （HCC） hepatectomy.Methods A total of 260 patients with HCC who underwent hepatectomy were enrolled.HCC tissues and tumor adjacent tissues which were 2 cm away from the tumor edge of the patients were obtained.The clinicopathological data of patients were collected.The methylation of RASSF1A in HCC tissues and corresponding tumor adjacent tissues was determined by methylation specific polymerase chain reaction （PCR）.The correlation between the expression rate of RASSF1A methylation and clinicopathological characteristics was analyzed by chi-square test.Log-rank test was performed to analyze the relation between RASSF1A methylation and overall survival rate.Univariate and multivariate Cox statistical techniques were used to identify the influence factors in the prognosis of HCC.Results Among 260 HCC tissues and corresponding tumor adjacent tissues,RASSF1A promoter hypermethylation was detected in 214 HCC tissues （82.3 %） and 101 corresponding tumor adjacent tissues （38.8%）,and the difference was statistically significant （x2 =102.824,P 〈 0.01）.There was no correlation between RASSF1A methylation and age,gender,liver cirrhosis,α-fetoprotein level,maximum diameter of tumor,Barcelona Clinic Liver Cancer （BCLC） stage,hepatitis B virus （HBV） infection,smoking and alcohol drinking （all P〉0.05）.The 5-year overall survival rate of patients with negative RASSF1A methylation was 93%,while that of patients with positive RASSF1A methylation was 51 %,and the difference in overall survival rate between the two groups was statistically significant （x2 =26.556,P 〈 0.01）.Univariate and multivariate Cox regression analysis indicated that liver cirrhosis,BCLC stage and RASSF1A methylation were the main influence factors in the death of patients with HCC after surgery （Wald=16.767,8.791,16.286; all P〈0.01）.Conclusion RASSF1A methylation is not only one of the predictive factors of survival rate in patients with HCC after hepatectomy,but also an independent prognostic factor of HCC.