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Page 8 of 15 Zacharakis et al. Hepatoma Res 2018;4:65 I http://dx.doi.org/10.20517/2394-5079.2018.76

of HCC, which are recommended to be used in combination with the conventional HCC biomarker AFP to
improve the accuracy of HCC diagnosis because of lack of robustness [97,98] . Finally, the monitoring of cfDNA in
[99]
the urine has been recently reported to be a promising tool to predict HCC recurrence .

Proteomic analysis and serum metabolite biomarkers
An array of proteomic studies coupled with bioinformatics analysis identified serum protein fragments with
differential expression in HCC, which possibly could serve as potential HCC biomarkers [100] . Luo et al. [100]
investigated the utility of a serum metabolite biomarker panel of phenylalanyl-tryptophan and glycocholate.
They found a higher diagnostic performance for the serum metabolite biomarkers compared with the AFP in
terms of differentiating HCC from a high-risk population of cirrhosis.

Core-fucosylated
[101]
Core-fucosylated (CF) proteins could be candidate biomarkers in the diagnosis of HCC . CF such as from
fibronectin at site 1007 could differentiate HCC from cirrhosis in patients with alcoholic liver diseases.
Also, CF cadherin-5 at site 61 could distinguish between HCC on chronic HCV hepatitis liver disease from
cirrhosis. Furthermore, four differentially expressed apolipoprotein isoform proteins could differentiate
NAFLD without cirrhosis form NAFLD-related cirrhosis or HCC on cirrhotic NAFLD [102] . Also, another
protein, CD5 antigen-like, a soluble scavenger cysteine-rich protein that modulates inflammatory responses,
could distinguish between NAFLD-related cirrhosis from NAFLD without cirrhosis but could not have any
diagnostic value for HCC.

Finally, an 11-peak algorithm based on analysis of serum proteins was proven to be more accurate than several
[103]
conventional biomarkers for early-stage HCC . Overall, more proteomics probably will identify more HCC
biomarkers.

DEVELOPMENT OF NEW HCC BIOMARKERS FOR DIAGNOSIS, PROGNOSIS AND TUMOR
RESPONSE PREDICTION
So far, none of the new biomarkers outperform the conventional ones in such a way that it has been widely
adopted in clinical practice. However, new data are promising.

Biomarkers for HCC risk assessment
Cirrhotic patients undergo justified periodical screenings to detect the early development of HCC. The
identification of host factors such as the various biological pathways involved in liver carcinogenesis may help
define specific adapted screening policies. Today, numerous candidate-gene studies have reported associations
[104]
between SNPs and the presence of HCC .
Unfortunately, the several host SNPs identified so far only partly explain the association with HCC in
HCV‐infected patients and did not enable good prediction on the individual and population levels [105] . It
seems reasonable that various panels of SNPs should be incorporated into complex models of “genomic
risk prediction”, which take into account both host and environmental factors that can influence liver
carcinogenesis at the near future.

At present, two biomarkers for HCC risk assessment have been developed including SNPs in germ-line
epidermal growth factor associated with HCC on HCV-related cirrhosis and a specific 186-gene signature
[106]
defining the high risk of HCC development in cirrhotic patients .

Biomarkers for HCC diagnosis
[107]
Non-invasive diagnosis using EASL/AASLD criteria allows a confidential diagnosis of most HCCs above 2 cm .
However, imaging is less reliable in one-third of small nodules, and a liver biopsy is often indicated. In this