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Zacharakis et al. Hepatoma Res 2018;4:65 I http://dx.doi.org/10.20517/2394-5079.2018.76 Page 5 of 15

[46]
with AFP-L3 fraction levels . Serum DCP-based diagnosis showed suboptimal sensitivity (48%-62%) but
satisfactory specificity (81%-98%) in HCC patients [43,47] .

Regarding the role of PIVKA-II as treatment response marker, a recent meta-analysis showed that increased
PIVKA-II levels could predict worsening overall survival and recurrence-free survival in patients with HCC
[48]
who had curative ablation . More studies are needed to confirm the clinical utility of PIVKA-II for HCC
prognosis. At present, none of the above surveillance tests can be recommended to screen patients at high risk
for HCC.

Surveillance tests: the combination of AFP + AFP-L3 + DCP markers
To address the problem of the markers being suboptimal due to sensitivity and specificity problems,
combined application of DCP- and AFP-based biomarkers has been tested. The combination of AFP-L3, AFP
and DCP markers used in 104 patients with HCC, 43% of whom had AFP levels below 10 ng/mL achieved
[49]
60.6% sensitivity and 100% specificity . In another large multicenter case-control study, DCP with AFP
immunoassay for HCC detection showed increased sensitivity from 65% to 87%, but specificity dropped from
[50]
84% to 69% . These studies supported the clinical utility of DCP for early-stage HCC diagnosis. However,
further studies are needed to validate the effectiveness of DCP alone or as part of a new predictive score for
HCC diagnosis. At present, the combination of AFP + AFP-L3 + DCP is included in the diagnostic algorithm
of hepatic nodules by Oriental guidelines for HCC management, but not by Western guidelines.

Other biomarkers
In an effort to identify markers with highest sensitivity and specificity for the detection of HCC, many other
molecules have been explored, including GPC3, GS, HSP70 (tissue), CK19, GP73, midkine, OPN, SCCA,
Annexin A2, FGF3/4, miRNAs, lncRNA, CTCs, and cfDNA. Also, biomarkers obtained by proteomic-based
approaches should be taken into account.

Proteomic studies have now identified multiple serum protein fragments with differential expression in HCC
such as 70-kDa HSP70 and fructose-1, 6-bisphosphatase 1, the most consistently reported proteins, with
[51]
upregulation and downregulation, respectively, in HCC . Therefore, many of these proteins could serve
as new biomarkers for HCC diagnosis, surveillance, prognosis, and treatment response. However, there is a
limitation of proteomics currently used, the lack of agreement among various studies in reporting changes in
protein expression associated with HCC.

Likewise, metabolomic studies investigate changes in lipid- and water-soluble metabolites found in the blood
or urine. The scope was to identify a broader array of potential biomarkers for HCC [52-54] . Also, glycomic
[55]
studies investigated N-glycosylation patterns that may be associated with cancer development . N-glycans
are complex polysaccharides bound to biomolecules through N-glycosylation and actively involved in several
biological processes.

Also, genetic signatures can also be included among oncomarkers with prognostic meaning. Genomic variation
[56]
between individuals has revealed multiple single nucleotide polymorphisms (SNPs) associated with HCC risk .
However, the high degree of change in gene expression based on patient ethnicity and underlying chronic liver
disease makes it difficult to discover gene expression profiles that can reliably predict the risk of HCC.

In conclusion, many molecules have been explored as possible biomarkers for HCC, and some of them are
described below.

GPC3, GS, HSP70
GPC3 is a cell-surface proteoglycan of the glypican family. This proteoglycan is overproduced in HCC cells
and plays a pivotal role in regulating tumor growth. So, the soluble NH2-terminal fragment of GPC3 is