J Liver Cancer.  2022 Sep;22(2):167-177. 10.17998/jlc.2022.09.19.

The diagnostic value of circulating tumor DNA in hepatitis B virus induced hepatocellular carcinoma: a systematic review and meta-analysis

• Chang Y
• Jeong SW
• Jang JY
• Eun H
• Lee Y
• Song DS
• Yu SJ
• Lee SH
• Kim W
• Lee HW
• Kim SG
• Ryu S
• Park S

• KMID: 2534243
• DOI: http://doi.org/10.17998/jlc.2022.09.19

Abstract

Background
/Aim: New biomarkers are urgently needed to aid in the diagnosis of early stage hepatocellular carcinoma (HCC). We performed a meta-analysis on the diagnostic utility of circulating tumor DNA (ctDNA) levels in patients with hepatitis B virus-induced HCC.
Methods
We retrieved relevant articles from PubMed, Embase, and the Cochrane Library up to February 8, 2022. Two subgroups were defined; one subset of studies analyzed the ctDNA methylation status, and the other subset combined tumor markers and ctDNA assays. Pooled sensitivity (SEN), specificity (SPE), positive likelihood ratio (PLR), negative likelihood ratio (NLR), diagnostic odds ratio (DOR), and area under the summary receiver operating characteristic curve (AUC) were analyzed.
Results
Nine articles including 2,161 participants were included. The overall SEN and SPE were 0.705 (95% confidence interval [CI], 0.629-0.771) and 0.833 (95% CI, 0.769-0.882), respectively. The DOR, PLR, and NLR were 11.759 (95% CI, 7.982-17.322), 4.285 (95% CI, 3.098- 5.925), and 0.336 (0.301-0.366), respectively. The ctDNA assay subset exhibited an AUC of 0.835. The AUC of the combined tumor marker and ctDNA assay was 0.848, with an SEN of 0.761 (95% CI, 0.659-0.839) and an SPE of 0.828 (95% CI, 0.692-0.911).
Conclusions
Circulating tumor DNA has promising diagnostic potential for HCC. It can serve as an auxiliary tool for HCC screening and detection, especially when combined with tumor markers.

Keyword

Carcinoma, hepatocellular; Circulating tumor DNA; Biomarkers; Diagnosis

Figure

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  Figure 1. A PRISMA flow diagram of the literature search. PRISMA, Preferred Reporting Items for Systematic Reviews and Meta-Analyses; ctDNA, circulating tumor DNA; Hcc, hepatocellular carcinoma; HbV, hepatitis b virus; cNA, copy number aberration; SEN, sensitivity; SPE, specificity.

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  Figure 2. Quality assessment of the included studies using the revised QUADAS-2. QUADAS-2, Quality Assessment of Diagnostic Accuracy Studies-2.

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  Figure 3. Forest plots of sensitivity and specificity of ctDNA assay for diagnosing HbV-related Hcc. (A) Overall ctDNA assay. (b) ctDNA methylation. (c) ctDNA assay combined with tumor markers. ctDNA, circulating tumor DNA; HbV, hepatitis b virus; Hcc, hepatocellular carcinoma.

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  Figure 4. SROc curves of diagnostic value for ctDNA assay for diagnosing HbV-related Hcc. (A) Overall ctDNA assay. (b) ctDNA methylation. (c) ctDNA assay combined with tumor markers. SROc, summary receiver operating characteristic; ctDNA, circulating tumor DNA; HbV, hepatitis b virus; Hcc, hepatocellular carcinoma.

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  Figure 5. Funnel plots to evaluate the publication bias for ctDNA assay for diagnosing HbV-related Hcc. (A) Overall ctDNA assay. (b) ctDNA methylation. (c) ctDNA assay combined with tumor markers. ctDNA, circulating tumor DNA; HbV, hepatitis b virus; Hcc, hepatocellular carcinoma.

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