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Guerriero et al. Hepatoma Res 2019;5:6  I  http://dx.doi.org/10.20517/2394-5079.2018.108                                       Page 3 of 22


               Table 1. Cell-free DNA as biomarker of hepatocellular carcinoma
                Target              Serum/     Technology   Experimental     Clinical setting  Cohort comparison  Ref.
                                    plasma                        setting
                DNA abundance       Plasma     Fluorimeter  cfDNA levels  Diagnosis   HCC vs. HBV-related LF [15]
                DNA abundance       Serum      Branched DNA  cfDNA levels  Diagnosis  HCC vs. HL     [114]
                DNA abundance       Plasma     Spectrophotometer cfDNA levels  Prediction of   HCC   [19]
                                                                         radiotherapy
                                                                         response
                DNA abundance       Plasma     Fluorimeter  cfDNA levels  Prognosis   HCC            [115]
                GSTP1               Serum      Real-time PCR  cfDNA levels  Diagnosis  HCC vs. HCV carriers  [16]
                GSTP1               Serum      Real-time PCR  cfDNA levels  Prognosis  HCC           [17]
                hTERT               Plasma     Real-time PCR  cfDNA levels  Diagnosis  HCC vs. CHC + LC  [18]
                hTERT               Plasma     Real-time PCR  cfDNA levels  Prognosis  HCC           [18]
                APC, FHIT, p15, p16, E-cadherin Plasma  MSP  Methylation  Diagnosis   HCC 1          [116]
                APC, GSTP1, RASSF1A, SFRP1  Plasma  MSRE-qPCR  Methylation  Diagnosis  HCC vs. HL    [21]
                APC, GSTP1, RASSF1A, SFRP1  Plasma  MSRE-qPCR  Methylation  Diagnosis  HCC vs. BLD   [21]
                APC, GSTP1, RASSF1A, SFRP1  Plasma  MSRE-qPCR  Methylation  Prognosis  HCC           [21]
                Gene panel (12 genes)  Plasma  NGS          Methylation  Diagnosis     HCC vs. CLD + HL   [25]
                p15, p16            Plasma     MSP          Methylation  Diagnosis/   HCC vs. CLD + HL  [23]
                                                                         prognosis
                SEPT9               Plasma     MSP          Methylation  Diagnosis    HCC vs. LC     [117]
                SOCS3               Plasma     MSP          Methylation  Diagnosis/   HCC vs. LC, BLD + HL  [24]
                                                                         prognosis
                UBE2Q1              Serum      MSP          Methylation  Diagnosis    HCC vs. LC + CHB  [118]
                Gene panel          Plasma     NGS          Mutations    Guiding therapy   HCC       [31]
                                                                         choice
                Gene panel (574 genes)  Plasma  NGS         Mutations    Tumor        HCC 1          [32]
                                                                         heterogeneity and
                                                                         prognosis
                Gene panel (58 genes)  Plasma/serum NGS     Mutations    Patient monitoring  HCC 1   [27]
                KRAS, NRAS          Plasma     BEAMing      Mutations    Guiding therapy   HCC       [31]
                                                                         choice
                TERT                Plasma     ddPCR        Mutations    Diagnosis    HCC vs. LC     [119]
                TERT                Plasma     ddPCR        Mutations    Prognosis    HCC            [119]
                TERT, CTNNB1, TP53  Plasma     NGS          Mutations    Prognosis    HCC 1          [120]
                TP53                Plasma     ddPCR        Mutations    Diagnosis    HCC vs. CLD + HL  [26]
                TP53                Plasma     COLD-PCR     Mutations    Patient monitoring  HCC     [121]
                TP53, CTNNB1, TERT  Plasma     ddPCR        Mutations    Diagnosis    HCC 1          [28]
                Genome-wide         Plasma     NGS          CNV          Diagnosis    HCC vs. CH + LC  [122]
                Genome-wide         Plasma     NGS          SNV, CNV     Diagnosis    HCC vs. HL     [123]
                Genome-wide         Plasma     NGS          SNV, CNV     Patient monitoring  HCC     [123]
                Gene panel (54-70 genes)  Plasma  NGS       SNV, CNV, fusions  Guiding therapy   HCC  [29]
                                                                         choice
               1 Tumor DNA vs. matched cfDNA. GSTP1: glutathione S-transferase p1; hTERT: telomerase reverse transcriptase; APC: adenomatous
               polyposis coli; FHIT: fragile histidine triad; p15: cyclin dependent kinase inhibitor 2B; p16: cyclin dependent kinase inhibitor 2A; RASSF1A:
               ras association domain family member 1; SFRP1: secreted frizzled related protein 1; SEPT9: septin 9; SOCS3 : suppressor of cytokine
               signaling 3; UBE2Q1: ubiquitin conjugating enzyme E2 Q1; KRAS: KRAS proto-oncogene; NRAS: NRAS proto-oncogene; CTNNB1: beta
               catenin 1; TP53: tumor protein p53; MSP: methylation-specific PCR; MSRE-qPCR: methylation-sensitive restriction enzymes qPCR;
               NGS: next generation sequencing; BEAMing: beads, emulsion, amplification, and magnetics PCR; ddPCR: droplet digital PCR; CNV:
               copy number variations; SNV: single nucleotide variations; cfDNA: cell-free DNA; BLD: benign liver disease; CH: chronic hepatitis; LF:
               liver fibrosis; CHB: chronic hepatitis B; CHC: chronic hepatitis C; CLD: chronic liver disease; HBV: hepatitis B virus; HCC: hepatocellular
               carcinoma; HL: healthy liver; LC: liver cirrhosis; HCV: hepatitis C virus

               displayed 87.0% sensitivity and 100% specificity as diagnostic performance . As a surrogate of abundance
                                                                              [15]
               of circulating DNA, some studies evaluated the amount of cfDNA by quantifying specific circulating gene
               fragments. Iizuka et al.  found a significant increase in serum levels of the GSTP1 gene in HCC patients
                                   [16]
               and found correlations with tumor grade and size. An increased GSTP1 gene in cfDNA was also associated
                                                                     [17]
               with a shorter overall survival (OS) and metastasis occurrence . Similarly, higher than normal levels of
                                                                                                       [18]
               hTERT gene in plasma of HCC patients correlated with presence of advanced disease and shorter survival .
               Quantification of cfDNA revealed its potential usefulness also for assessing therapy response. Reduction of
                                                                             [19]
               plasma cfDNA after radiotherapy correlated with a better tumor response .
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