SFRP1、LINE1基因启动子区CpG岛甲基化状态在肝细胞癌预后评估的价值

The Evaluation Value of Methylation Status of CpG Island of SFRP1 and LINE1 Gene Promoter Area in the Prognosis of Hepatocellular Carcinoma

目的探讨分泌型卷曲相关蛋白(SFRP)1、长散在核元件(LINE)1基因启动子区CpG岛甲基化与人原发性肝癌(简称肝癌)临床病理参数的关系,及其在肝癌预后评估的意义。方法收集105例肝癌患者血浆和50例对照健康人血浆DNA,使用甲基化特异性PCR(MSP)检测了SFRP1基因启动子区CpG岛高甲基化和LINE1基因启动子区CpG岛低甲基化的情况;分析两种基因启动子甲基化和肝癌患者临床病理参数之间的关系;通过Kaplan-Meier曲线、对数秩检验及Cox多因素分析,分析SFRP1、LINE1基因甲基化状态与肝癌患者总生存率及无病生存率之间的关系。结果105例肝癌患者血浆中SFRP1基因启动子区CpG岛高甲基化阳性率为59.05%(62/105),LINE1基因启动子区CpG岛低甲基化率为66.67%(70/105),基因SFRP1高甲基化和LINE1低甲基化表达均阳性为43.81%(46/105),正常对照组中未发现有这两种基因甲基化;SFRP1高甲基化、LINE1低甲基化均与HBsAg是否阳性及甲胎蛋白(AFP)值相关(P<0.05);SFRP1、LINE1基因启动子区域的甲基化状态与总生存率及无病生存率有关:SFRP1高甲基化阴性+LINE1低甲基化阴性组患者预后最好,而SFRP1高甲基化阳性+LINE1低甲基化阳性组患者预后最差。结论 SFRP1、LINE1基因启动子区CpG岛甲基化与肝癌的发生、发展有一定联系,SFRP1和LINE1基因甲基化状态可以作为潜在可靠的分子标记物对患者预后进行预测。

Objective To investigate the relationship between aberrant promoter CpG islands methylation status of secreted frizzled related protein 1 （SFRP1） and long intersper sed nuclear element 1 （LINE1） gene and clinicopathologic parameters to determine their prognosis value for hepatocellular carcinoma （HCC）. Methods 105 cases of HCC and 50 cases of normal people plasma were collected, and then the promoter hypermethylation status of SFRP1 and hypormethylation status of LINE1 were examined by methylation specific PCR （MSP）; The relationship between SFRP1/LINE1 methylation status and patients＇ clinicopathologic factors was analyzed; The association between SFRP1/LINE1 methylation status and disease-free survival and overall survival was analyzed by Kaplan-Meier curves, the log-rank test, and multivariate Cox regression. Results SFRP1 gene promoter CpG islands hypermethylation and LINE1 gene promoter CpG islands hypomethylation were found in 59.05% （62/105） and 66.67% （70/105） of 105 cancerous plasma cases, repectively, SFRP1 hypermethylation status and LINE1 hypomethylation status in plasma of HCC account for 43.81 %（62/105） and no positive methylation cases were detected in normal cases＇ The hypermethylation status of SFRP1 and hypomethylation status of LINE1 gene were related with HBsAg and a-fetoprotein （AFP） level; There was statistically significant difference between CpGislands hypermethylation of two genes and disease-free survival rate and overall survival rate~ The group patients with SFRP1 hypermethylation positive and LINE1 hypomethylation positive demonstrated the worst prognosis while the group with SFRP1 hypermethylation negative and LINE1 hypomethylation negative had the best prognosis. Conclusion The promoter methylation of SFRP1 and LINE1 is correlated with the occurrence and development of HCC. SFRP1 and LINE1 might be potential and reliable biomarkers for predicting prognosis in HCC patients.