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Page 2 of 15 Zacharakis et al. Hepatoma Res 2018;4:65 I http://dx.doi.org/10.20517/2394-5079.2018.76

Other risk factors include metabolic disorders such as nonalcoholic fatty liver disease (NAFLD) and chronic
[4]
alcohol consumption . The frequency of cirrhosis among patients with HCC has been shown to be 85%-
[7]
[5,6]
95% . The HCC incidence rate among cirrhotic patients has been estimated to be 2%-4% per year . Cirrhotic
patients represent a high-risk group for HCC development and should undergo surveillance for HCC on a
regular basis.

Early detection of HCC through surveillance methods have increased patient survival by providing effective
[8,9]
initial treatments such as primary curative hepatectomy and locoregional ablative therapy . Surveillance
and diagnostic methods for HCC depend on several biomarkers, defined as molecules that can be objectively
measured in body fluids.

Although many studies have investigated several biomarkers for the prognosis and the evaluation of HCC, no
biomarkers can predict and/or confirm the presence of HCC. There are no validated predictive biomarkers to
evaluate the therapeutic response to HCC treatment except for the alpha-fetoprotein (AFP) for the evaluation
[10]
of ramucirumab treatment efficacy as recently presented by Zhu et al. .

The most well-studied HCC biomarkers are (1) the AFP, its isoform lens culinaris agglutinin-reactive fraction
of alpha-fetoprotein (AFP-L3); and (2) des-γ-carboxy prothrombin (DCP). However, there are many other
molecules that might be taken into account for future studies, including glypican 3 (GPC3), glutamine synthase
(GS), heat shock protein 70 (HSP70), cytokeratin 19 (CK19), Golgi protein 73 (GP73), midkine, osteopontin
(OPN), squamous cell carcinoma antigen (SCCA), Annexin A2, fibroblast growth factor 3/4 (FGF3/4), micro-
RNAs (miRNAs), Long non-coding RNAs (lncRNAs), circulating tumor cells (CTCs), cell-free DNA (cfDNA),
and other biomarkers based on proteomic analyses. In addition, genetic signatures might play a role in the
[9]
prognosis of HCC and therefore, they might be considered among possible disease biomarkers .

Epigenetic modifications are the changes occurring in the gene expression but do not involve changes in the
DNA sequence. These modifications include DNA methylation and histone modifications. Interestingly, some
enzymes involved in the epigenetic regulation have shown to be involved in HCC pathogenesis. These enzymes
include RASSF1A, P16, DLC1 RhoA GTPase activating protein, runt related transcription factor 3, and
suppressor of cytocine signaling 1 [11,12] . Multiple studies showed that (1) targeting these epigenetic modifiers
might be effective in different types of cancers including HCC; and (2) they have the potential to be used as
biomarkers for therapeutic response [13,14] . Histone deacetylase inhibitors such as panalinostat and belinostat
have shown therapeutic efficacy in HCC [15,16] .

CURRENTLY USED BIOMARKERS AND LIMITATIONS OF OLD BIOMARKERS
AFP for HCC surveillance in high-risk groups, diagnosis, and prognosis. Is it the ideal biomarker
AFP is the most extensively used old biomarker. AFP is a common biomarker for the diagnosis and
surveillance for HCC and it has reached the phase 5 of biomarker development stages (prospective randomized
studies aiming to define the clinical utility of biomarkers).

[17]
AFP is a large serum glycoprotein that is a part of the serum albumin gene family . The synthesis of AFP
[18]
in the liver occurs during the fetal life is repressed during the adulthood . Therefore, AFP levels often
diminish rapidly after birth and remain low throughout the adulthood. However, AFP can be expressed
under certain pathological conditions such as chronic liver disease, HCC, germ cell tumors, and gastric
[19]
cancer .

There have been several investigations concerning the diagnostic utility of AFP suggesting that elevated serum
AFP levels (> 20 ng/mL) correlate with an increased risk for HCC development. Although the sensitivity of
AFP is excellent, its specificity is low. The use of a higher cutoff value such as of 200 ng/mL drops the sensitivity