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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



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               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 .
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