Using circulating tumor DNA as a novel biomarker to screen and diagnose hepatocellular carcinoma: A systematic review and meta-analysis

Cancer Med. 2020 Feb;9(4):1349-1364. doi: 10.1002/cam4.2799. Epub 2019 Dec 26.


Purpose: A meta-analysis was formulated to appraise the diagnostic accuracy of circulating tumor DNA (ctDNA) in hepatocellular carcinoma (HCC).

Materials and methods: We enrolled all relevant studies published until September 2019. Four primary subgroups were investigated: the subgroup of quantitative or qualitative analysis of ctDNA, the subgroup of Ras association domain family 1 isoform A (RASSF1A) methylation in ctDNA and the subgroup of the combined alpha-fetoprotein (AFP) and ctDNA assay. We analyzed the pooled sensitivity (SEN), specificity (SPE), positive likelihood ratio (PLR), negative likelihood ratio (NLR), diagnostic odds ratio (DOR), and summary receiver operating characteristic (SROC) as well as the area under the curve (AUC).

Results: A total of 33 qualified articles with 4113 subjects were incorporated into our meta-analysis. The combined SEN, SPE, and DOR in quantitative studies were 0.722 (95% confidence interval (95% CI): 0.686-0.756), 0.823 (95% CI: 0.789-0.854), 18.532 (95% CI: 8.245-41.657), respectively, yielding an AUC of 0.880. For qualitative studies, the corresponding value was 0.568 (95% CI: 0.548-0.587), 0.882 (95% CI: 0.867-0.897), 10.457 (95% CI: 7.270-15.040) and 0.787, respectively. Detection of RASSF1A methylation yielded an AUC of 0.841, with a SEN of 0.644 (95% CI: 0.608-0.678) and a SPE of 0.875 (95% CI: 0.847-0.900). AFP combined with ctDNA assay achieved an AUC of 0.944, with a SEN of 0.760 (95% CI: 0.728-00.790) and a SPE of 0.920 (95% CI: 0.893-00.942).

Conclusion: Circulating tumor DNA displays a promising diagnostic potential in HCC. However, it is not independently sufficient and can serve as an assistant tool combined with AFP for HCC screening and detection.

Keywords: circulating tumor DNA; diagnostic accuracy; hepatocellular carcinoma; meta-analysis; methylation.

Publication types

  • Evaluation Study
  • Meta-Analysis
  • Research Support, Non-U.S. Gov't
  • Systematic Review

MeSH terms

  • Carcinoma, Hepatocellular / blood
  • Carcinoma, Hepatocellular / diagnosis*
  • Carcinoma, Hepatocellular / genetics
  • Circulating Tumor DNA / blood*
  • DNA Methylation
  • Humans
  • Liver Neoplasms / blood
  • Liver Neoplasms / diagnosis*
  • Liver Neoplasms / genetics
  • Mass Screening / methods*
  • Predictive Value of Tests
  • ROC Curve
  • Tumor Suppressor Proteins / genetics
  • alpha-Fetoproteins / analysis*


  • AFP protein, human
  • Circulating Tumor DNA
  • RASSF1 protein, human
  • Tumor Suppressor Proteins
  • alpha-Fetoproteins