循环肿瘤DNA在乙肝病毒性肝细胞癌中诊断价值的meta分析

Diagnostic value of circulating tumor DNA in hepatitis B virus-related hepatocellular carcinoma:a meta-analysis

目的系统评价循环肿瘤DNA(circulating tumor DNA,ctDNA)对乙肝病毒性肝细胞癌(hepatitis B viral hepatocellular carcinoma,HBV-HCC)的诊断效能,探讨ctDNA的临床应用价值。方法系统检索PubMed、Embase、Web of Science和Cochrane Library数据库,检索年限为建库至2021年4月26日。提取出文献的特征信息及敏感度、特异度和受试者工作特征(receiver operating characteristic,ROC)曲线下面积(area under curve,AUC)原始数据。采用RevMan 5.3和Stata 14.0软件进行meta分析,计算合并敏感度、合并特异度、阳性似然比、阴性似然比及诊断比值比(odds ratio,OR);绘制汇总ROC曲线并计算AUC;绘制Deek’s漏斗图评估发表偏倚;绘制Fagan图检测诊断效能。结果本研究最终纳入16篇文献共3744例患者,其中1852例为HBVHCC患者,1892例为无HCC的HBV感染患者。meta分析结果显示:ctDNA对HBV-HCC诊断的汇总敏感度、特异度和诊断OR分别为0.85[95%CI为(0.78,0.90)]、0.74[95%CI为(0.63,0.83)]和15.98[95%CI为(10.65,23.99)],汇总ROC的AUC为0.87[95%CI为(0.84,0.90)]。ctDNA联合AFP检测对HBV-HCC诊断的汇总敏感度、特异度和诊断OR分别为0.86[95%CI为(0.80,0.90)]、0.79[95%CI为(0.68,0.87)]和22.69[95%为(13.64,37.76)],汇总ROC的AUC为0.90[95%CI为(0.87,0.92)]。meta回归分析发现异质性来源于其他非协变量因素。Fagan图显示,若经基于ctDNA的液体活检诊断为HBV-HCC时,其确诊为HCC的概率为77%;如若为阴性结果,则患有HBV-HCC的概率则为17%。Deek’s检验未见明显发表偏倚(P>0.05)。结论ctDNA能以较高的敏感度、特异度和准确率诊断HBV-HCC,可以作为HBV相关HCC早期诊断中有希望的循环生物标志物。血清ctDNA联合AFP检测有利于提高HBV-HCC的诊断准确性。

Objective To systematically evaluate the diagnostic efficacy of circulating tumor DNA(ctDNA)in hepatitis B viral hepatocellular carcinoma(HBV-HCC),and to study the clinical value of ctDNA.Methods The databases of PubMed,Embase,Web of Science,and Cochrane Library database were retrieved systematically from the establishment of the database to April 26,2021.The characteristic information of literatures and the original data such as the sensitivity,specificity,and area under curve(AUC)of the receiver operating characteristic(ROC)curve were extracted.A meta-analysis was conducted by applying RevMan 5.3 and Stata 15.0 software.The combined sensitivity,combined specificity,positive likelihood ratio,negative likelihood ratio,and diagnostic odds ratio(OR)were calculated,ROC curve was plotted and the AUC was calculated,Deck’s funnel chart to assess publication bias,the Fagan diagram to test the diagnostic efficiency.Results Finally,16 studies involving 3744 patients were enrolled in this study,of which1852 were HBV-HCC patients,and 1892 were HBV-infected patients without HCC.The meta-analysis results showed that ctDNA had a pooled sensitivity of 0.85[95%CI(0.78,0.90)],a specificity of 0.74[95%CI(0.63,0.83)],a diagnostic OR of 15.98[95%CI(10.65,23.99)],and the AUC of ROC was 0.87[95%CI(0.84,0.90)]in the diagnosis of HBV-HCC.The pooled sensitivity,specificity,diagnostic OR,and the AUC of ROC for ctDNA combined with AFP in the diagnosis of HBV-HCC were 0.86[95%CI(0.80,0.90)],0.79[95%CI(0.68,0.87)],22.69[95%CI(13.64,37.76)],and 0.90[95%CI(0.87,0.92)].Meta-regression analysis found that the heterogeneity came from other non-covariate factors.The Fagan chart showed that while HBV-HCC was diagnosed by liquid biopsy-based on ctDNA,the probability of being diagnosed with hepatocellular carcinoma was 77%,if HBV-HCC was excluded,the probability of having the corresponding disease was17%.Deek’s test showed no obvious publication bias(P>0.05).Conclusions The ctDNA can diagnose HBV-HCC with high sensitivity,specificity and accuracy,and can be used as a promising circulating biomarker in the early diagnosis of HBV-related HCC.The combination of ctDNA in serum and AFP is beneficial to improve the diagnostic accuracy of HBV-HCC.