Diagnostic performance of circulating tumor DNA as a minimally invasive biomarker for hepatocellular carcinoma: a systematic review and meta-analysis

Jia Jie Li; Yanqing Lv; Huifan Ji

doi:10.7717/peerj.14303

Diagnostic performance of circulating tumor DNA as a minimally invasive biomarker for hepatocellular carcinoma: a systematic review and meta-analysis

PeerJ. 2022 Nov 3:10:e14303. doi: 10.7717/peerj.14303. eCollection 2022.

Authors

Jia Jie Li¹, Yanqing Lv², Huifan Ji²

Affiliations

¹ Hepatobiliary Pancreatic Department, The First Hospital of Jilin University, Changchun, Jilin, China.
² Department of Hepatobiliary and Pancreatic Medicine, The First Hospital of Jilin University, Changchun, Jilin, China.

Abstract

Purpose: This study aimed to assess the diagnostic performance of circulating tumor DNA (ctDNA) in hepatocellular carcinoma (HCC).

Materials and methods: We enrolled all relevant studies published up to 5 January 2022. Three primary subgroups were investigated: qualitative or quantitative ctDNA analyses, combined alpha-fetoprotein (AFP), and ctDNA assay. In addition to the three primary subgroups, we also evaluated the diagnostic value of methylated SEPTIN9 (mSEPT9), which has been studied extensively in the diagnosis of hepatocellular carcinoma. After a search based on four primary databases, we used a bivariate linear mixed model to analyze the pooled sensitivity (SEN), specificity (SPE), positive likelihood ratio (PLR), negative likelihood ratio (NLR), and diagnostic odds ratio (DOR). We also plotted hierarchical summary receiver operating characteristics (HSROC) and utilized lambda as well as the area under the curve (AUC) to create summary receiver operating characteristic (SROC) curves to estimate the diagnostic value of ctDNA.

Results: A total of 59 qualified articles with 9,766 subjects were incorporated into our meta-analysis. The integrated SEN, SPE, and DOR in the qualitative studies were 0.50 (95% CI [0.43-0.56]), 0.90 (95% CI [0.86-0.93]), and 8.72 (95% CI [6.18-12.32]), respectively, yielding an AUC of 0.78 and lambda of 1.93 (95% CI [1.56-2.33]). For quantitative studies, the corresponding values were 0.69 (95% CI [0.63-0.74]), 0.84 (95% CI [0.77-0.89]), 11.88 (95% CI [7.78-18.12]), 0.81, and 2.32 (95% CI [1.96-2.69]), respectively. Six studies were included to evaluate the SETP9 methylation, which yielded an AUC of 0.86, a SEN of 0.80 (95% CI [0.71-0.87]), and a SPE of 0.77 (95% CI [0.68-0.85]). Likewise, ctDNA concentration yielded an AUC of 0.73, with a SEN of 0.63 (95% CI [0.56-0.70]) and a SPE of 0.86 (95% CI [0.74-0.93]). AFP combined with ctDNA assay resulted in an AUC of 0.89, with a SEN of 0.82 (95% CI [0.77-0.86]) and a SPE of 0.84 (95% CI [0.76-0.90]).

Conclusion: This study shows that circulating tumor DNA, particularly mSEPT9, shows promising diagnostic potential in HCC; however, it is not enough to diagnose HCC independently, and ctDNA combined with conventional assays such as AFP can effectively improve diagnostic performance.

Keywords: DNA Methylation; Hepatocellular carcinoma; Meta-analysis; mSEPT9; Circulating tumor DNA; Diagnostic performance.

Publication types

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

MeSH terms

Carcinoma, Hepatocellular* / diagnosis
Circulating Tumor DNA* / genetics
Humans
Liver Neoplasms* / diagnosis
ROC Curve
alpha-Fetoproteins / analysis

Substances

alpha-Fetoproteins
Circulating Tumor DNA

Grants and funding

The authors received funding from the Jilin Provincial Health Special Project. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.