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Banini et al. Hepatoma Res 2019;5:34 I http://dx.doi.org/10.20517/2394-5079.2019.30 Page 7 of 10

A biomarker panel based on analysis of a number of genes may serve to better differentiate HCC blood
from normal samples, as shown for a combined analysis of the methylation pattern of four genes APC,
GSTP1, RASSF1A, and SFRP1 which showed an AUCROC of 0.933 in identifying HCC from normal
[67]
samples, compared to 0.800 to 0.881 for the individual genes . In another study to evaluate the potential
[74]
of ctDNA methylation patterns in the diagnosis and prognostication of HCC, Xu et al. identified a
methylation marker panel differentially enriched in HCC tissue compared to blood leukocytes of healthy
individuals. In a training data set of 715 HCC samples and 560 normal samples, the sensitivity and
specificity of a 10-marker panel based on methylation patterns were 85.7% and 94.3%, respectively, and
[74]
a combined prognostic score based on these markers significantly correlated with risk of death . These
studies suggest that methylation changes characteristic of HCC can be reliably identified in peripheral
blood samples and potentially serve as biomarkers for diagnosis and prognostication of HCC.

CONCLUSION
Liquid biopsy analysis of serum and plasma can reliably detect genetic and epigenetic alterations present in
HCC tumor tissue, providing a less invasive alternative to the current gold standard of liver biopsy. Due to
the significant heterogeneity of HCC, a single biomarker would lack the requisite sensitivity and specificity
for HCC diagnosis, hence a panel consisting of multiple genetic and epigenetic alterations, likely in
combination with protein biomarkers, would have the best diagnostic utility. One such test is CancerSEEK,
which detects eight tumor-associated protein biomarkers and mutations in 1933 distinct genomic positions,
with 98% sensitivity and 99% specificity for HCC detection when tested in 44 HCC patients and 812
[59]
[59]
controls . The authors estimated a cost of about $500 to perform a CancerSEEK analysis . Although
the test holds promise for diagnosing and monitoring HCC, further studies, including performance of the
assay in patients at high risk for HCC such as those with advanced fibrosis or cirrhosis would need to be
undertaken. Several other analyses of cfDNA biomarkers either alone or in combination with non-nucleic
acid biomarkers for non-invasive diagnosis of HCC are in progress.

DECLARATIONS
Authors’ contributions
Study concept and design: Banini BA, Sanyal AJ
Literature search: Banini BA
Drafting of the manuscript: Banini BA
Critical revision of the manuscript for important intellectual content: Banini BA, Sanyal AJ

Availability of data and materials
Not applicable.

Financial support and sponsorship
This work was supported by the NIH Grants (5T32 DK07150, RO1 DK 10596).

Conflicts of interest
Both authors declared that there are no conflicts of interest. Dr. Sanyal is President of Sanyal Biotechnology
and has stock options in Tiziana, Durect, Indalo, Inversago. He has served as a consultant to Medimmune,
Astra Zeneca, Nitto Denko, Nimbus, Salix, Tobira, Takeda, Terns, Conatus, Lilly, Poxel, Blade, Surrozen,
Birdrock, Siemens, Madrigal, Novartis, Pfizer, Hemoshear, Novo Nordisk, Gilead, Exhalenz, Bristol Myers
Squibb, Glympse and Genfit. He has been an unpaid consultant to Intercept, Zafgen, Prosciento, Iquvia,
NGM Bio, Echosens, Immuron, Syntlogic, Zafgen, Zydus, Nordic Bioscience. His institution has received
grant support from Gilead, Salix, Tobira, Intercept, Merck, Astra Zeneca, Zydus and Novartis.