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Page 4 of 22 Guerriero et al. Hepatoma Res 2019;5:6 I http://dx.doi.org/10.20517/2394-5079.2018.108

A

B

Figure 1. Liquid biopsies and their clinical applications. A: Liquid biopsy is an approach for detecting and analyzing DNA and RNA in
biological fluids, such as serum, plasma, urine and saliva. Being a minimally invasive procedure, it offers the possibility of performing
repeated sampling over time, thus providing a practical method for patient surveillance. Blood plasma or serum from patients contain
cancer derived material, such as CTCs, ctDNA, miRNAs and other RNAs; B: analysis of such DNA/RNA content can provide evidences
on the presence of HCC at an early stage, assessment of prognosis and patients’ monitoring during and after therapy, thus helping the
clinical management of patients at different phases of disease. CTC: circulating tumor cell; ctDNA: cell-free tumor DNA; ncRNA: non-
coding RNA

Quantification of circulating DNA is very easy to perform and inexpensive. However, this approach lacks
specificity for type of cancer; in addition, levels of cfDNA can also increase in inflammatory conditions
unrelated to cancer or in some physiological conditions, such as pregnancy. Furthermore, this analysis does
not provide information about tumor genetic landscape and cannot reveal actionable targets. For these
reasons, most investigations moved toward the detection of more specific genetic or epigenetic alterations in
blood, as biomarkers for HCC.

Aberrant methylation of cfDNA in plasma or serum in HCC
Promoter methylation is a well-known mechanism for gene transcriptional repression. Aberrant methylation
in promoters of cancer genes represents a tumor-specific event and its detection is potentially useful for the
prediction or diagnosis of HCC. Concordance between aberrant methylations in tumor tissues and plasma
is generally good, indicating that plasma could represent a tumor surrogate when tissue is not available.
The field has been widely investigated and a meta-analysis of these studies has been published . In the
[20]
diagnostic setting, from the analysis of 150 plasma samples from patients with HCC, benign liver disease
(including cirrhosis and chronic inactive hepatitis) and normal controls, Huang and co-workers found that
the combined aberrant methylation of four genes (APC, GSTP1, RASSF1A and SFRP1) has a significant
[21]
diagnostic value for HCC , confirming the results obtained in tumor tissues . In particular, the
[22]
combination analysis of plasma methylation levels of these genes allowed to discriminate HCC from both
benign or normal controls, with a sensitivity of 84.7% (in both cases) and a specificity of 81.1% and 87.8%
[21]
respectively .