循环肿瘤DNA对中国肝癌诊断价值的Meta分析

doi:10.3877/cma.j.issn.2095-3232.2022.06.015

目的

系统评价循环肿瘤DNA（ctDNA）在中国人群原发性肝癌（肝癌）中的诊断价值。

方法

检索PubMed、Web of Science、Embase、中国知网、万方、维普数据库中从建库至2021年11月关于应用ctDNA诊断肝癌的文献。中英文检索词为循环肿瘤DNA、ctDNA、游离DNA、循环DNA、cfDNA、血浆DNA、血清DNA，以及肝癌、肝细胞癌、肝肿瘤、肝脏肿瘤、原发性肝癌等。对纳入文献进行数据提取和质量评估后，采用Review Manager 5.3和Stata 15.1统计软件计算合并敏感度、特异度，绘制森林图和综合受试者操作特征（sROC）曲线并计算曲线下面积（AUC）。通过Meta回归分析和亚组分析分析异质性来源。绘制Deek's漏斗图检验发表偏倚。

结果

共纳入符合标准的文献25篇，包括4 063例肝癌患者和3 509例对照。其中5项研究为检测ctDNA浓度的定量分析，14篇为检测ctDNA中的肿瘤特异性单基因甲基化的定性分析，6篇通过ctDNA的特征构建模型进行诊断。定量研究组的合并敏感度、特异度及AUC分别为0.68（0.58~0.77）、0.82（0.71~0.89）和0.81（0.77~0.84）；定性研究组相应为0.55（0.47~0.62）、0.99（0.93~1.00）和0.80（0.77~0.83）；模型构建组相应为0.81（0.72~0.87）、0.91（0.85~0.94）和0.93（0.90~0.95）。Deek's漏斗图检验显示，定量研究组（t=1.080，P>0.05）、定性研究组（t=0.690，P>0.05）和模型构建组（t=0.230，P>0.05）均不存在明显的发表偏倚。

结论

ctDNA在我国肝癌诊断中具有良好的应用价值，利用ctDNA构建模型的诊断性能优于定量分析和定性分析。

关键词: 癌，肝细胞, 循环肿瘤DNA, 诊断试验, Meta分析

Objective

To systematically evaluate the diagnostic value of circulating-tumor DNA (ctDNA) in Chinese patients with primary liver cancer (PLC).

Methods

Literature related to ctDNA for the diagnosis of liver cancer were searched from PubMed, Web of Science, Embase, CNKI, Wanfang Data and Chongqing VIP databases from the inception date to November 2021. The searching terms included circulating-tumor DNA, ctDNA, free DNA, circulating DNA, cfDNA, plasma DNA, serum DNA, and liver cancer, hepatocellular carcinoma, liver tumor, primary liver cancer, etc. After data extraction and quality evaluation of the included studies, the combined sensitivity, specificity were calculated, the forest plot and summary receiver operating characteristic (sROC) curve were delineated and the area under the ROC curve (AUC) was calculated by Review Manager 5.3 and Stata 15.1 software. The heterogeneous sources were analyzed by Meta-regression analysis and subgroup analysis. The publication bias was assessed by Deek's funnel plot.

Results

25 literature were included, including 4 063 liver cancer patients and 3 509 controls. In 5 studies, quantitative analysis of the concentration of ctDNA was conducted, qualitative analysis of tumor-specific single-gene methylation in ctDNA was performed in 14 studies, and diagnostic models were constructed based on the characteristics of ctDNA in 6 studies. The combined sensitivity, specificity and AUC in the quantitative studies were 0.68(0.58-0.77), 0.82(0.71-0.89) and 0.81(0.77-0.84), 0.55(0.47-0.62), 0.99(0.93-1.00) and 0.80(0.77-0.83) in the qualitative studies, and 0.81(0.72-0.87), 0.91(0.85-0.94) and 0.93(0.90-0.95) in the model construction studies, respectively. Deek's funnel plot indicated that no significant publication bias was observed in quantitative studies (t=1.080, P>0.05), qualitative studies (t=0.690, P>0.05) and model construction studies (t=0.230, P>0.05).

Conclusions

ctDNA possesses high application value in the diagnosis of liver cancer in China. The diagnostic performance of ctDNA-based model is superior that of quantitative and qualitative analyses.

Key words: Carcinoma, hepatocellular, Circulating tumor DNA, Diagnostic test, Meta-analysis

图1 纳入文献质量评价

图2 ctDNA定量研究诊断肝癌的合并敏感度和特异度森林图注：ctDNA为循环肿瘤DNA

图5 ctDNA诊断肝癌的sROC曲线图注：ctDNA为循环肿瘤DNA，sROC为综合受试者操作特征

图3 ctDNA定性研究诊断肝癌的合并敏感度和特异度森林图注：ctDNA为循环肿瘤DNA

图4 利用ctDNA构建模型诊断肝癌的合并敏感度和特异度森林图注：ctDNA为循环肿瘤DNA

表1 ctDNA诊断肝癌Meta回归及亚组分析结果

分组		文献数（篇）	χ²值	P值	合并敏感度		合并特异度
分组		文献数（篇）	χ²值	P值	95%CI	P值	95%CI	P值
定性研究组
样本来源			10.68	<0.01		0.04		0.13
	血浆	9			0.49（0.40~0.58）		0.99（0.96~1.00）
	血清	4			0.65（0.54~0.76）		0.98（0.95~1.00）
模型构建组
研究类型			46.32	<0.01		0.16		<0.01
	前瞻性	2			0.86（0.75~0.97）		0.78（0.64~0.92）
	回顾性	7			0.85（0.79~0.92）		0.92（0.88~0.96）
地区			43.65	<0.01		0.86		<0.01
	南方	6			0.83（0.73~0.93）		0.82（0.76~0.88）
	北方	4			0.74（0.56~0.91）		0.95（0.91~0.98）
对照类型			7.65	0.02		0.14		0.14
	健康人	5			0.80（0.69~0.92）		0.95（0.91~0.98）
	良性肝病	7			0.80（0.70~0.90）		0.86（0.81~0.92）
肝癌病例数			6.79	0.03		0.47		<0.01
	≥100例	5			0.88（0.82~0.93）		0.86（0.79~0.93）
	<100例	7			0.71（0.62~0.81）		0.94（0.89~0.98）

表1 ctDNA诊断肝癌Meta回归及亚组分析结果

分组		文献数（篇）	χ²值	P值	合并敏感度		合并特异度
分组		文献数（篇）	χ²值	P值	95%CI	P值	95%CI	P值
定性研究组
样本来源			10.68	<0.01		0.04		0.13
	血浆	9			0.49（0.40~0.58）		0.99（0.96~1.00）
	血清	4			0.65（0.54~0.76）		0.98（0.95~1.00）
模型构建组
研究类型			46.32	<0.01		0.16		<0.01
	前瞻性	2			0.86（0.75~0.97）		0.78（0.64~0.92）
	回顾性	7			0.85（0.79~0.92）		0.92（0.88~0.96）
地区			43.65	<0.01		0.86		<0.01
	南方	6			0.83（0.73~0.93）		0.82（0.76~0.88）
	北方	4			0.74（0.56~0.91）		0.95（0.91~0.98）
对照类型			7.65	0.02		0.14		0.14
	健康人	5			0.80（0.69~0.92）		0.95（0.91~0.98）
	良性肝病	7			0.80（0.70~0.90）		0.86（0.81~0.92）
肝癌病例数			6.79	0.03		0.47		<0.01
	≥100例	5			0.88（0.82~0.93）		0.86（0.79~0.93）
	<100例	7			0.71（0.62~0.81）		0.94（0.89~0.98）

图6 ctDNA诊断肝癌研究的漏斗图注：a、b、c分别为定量研究组、定性研究组和模型构建组漏斗图；ctDNA为循环肿瘤DNA，DOR为诊断比值比，ESS为有效样本量

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Diagnostic value of circulating-tumor DNA in Chinese patients with primary liver cancer: a Meta-analysis

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Diagnostic value of circulating-tumor DNA in Chinese patients with primary liver cancer: a Meta-analysis