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Page 2 of 22 Guerriero et al. Hepatoma Res 2019;5:6 I http://dx.doi.org/10.20517/2394-5079.2018.108

INTRODUCTION
Hepatocellular carcinoma (HCC) is the most common type of liver cancer and second leading cause of
cancer-related deaths worldwide. Despite new therapeutic approaches, prognosis remains poor. According
[1]
to the Barcelona Clinic Liver Cancer (BCLC) system , treatment options rely on cancer staging. Patients
with an early stage HCC (BCLC stage A) can take advantage of curative treatments, such as tumor resection,
ablation and liver transplantation. Although termed curative, risk of recurrence in post-surgical resection is
[2]
about 70% at 5 years . Patients who presents an intermediate (Stage B) or advanced (Stage C) HCC, about
70% of the total, can only benefit from palliative treatments, chemoembolization or sorafenib respectively,
[3-5]
with survival in fewer than 10% of patients at 3 years .

Poor prognosis of HCC can be partly attributed to the fact that the majority of neoplasms are diagnosed at
intermediate or advanced stages. Availability of blood biomarkers would be extremely important to improve
early diagnosis in individual at risk or for a better management of prognosis and response to therapy in
HCC patients. Among biomarkers presently in use, alpha fetoprotein (AFP) and des-g-carboxy prothrombin
[6]
(DCP) are the most commonly employed. AFP was the most widely used serum biomarker in HCC , but
[7-9]
due to suboptimal sensitivity (55%-65%) , it is now employed to the monitoring of therapy effectiveness in
HCC patients, together with ultrasound examination. DCP is a second biomarker utilized in HCC; although
[10]
initially indicated as superior to AFP with a sensitivity of 92% and specificity of 93% , other studies showed
suboptimal sensitivity (48%-62%) [11,12] . These studies signify that more effective biomarkers are needed for
better management of HCC patients at various clinical phases.

Since 80%-90% of HCCs develop in a cirrhotic liver, a distinction between regenerative nodules and early
[13]
HCC can be a challenge . Albeit DCP exhibits the potential capability of differentiating HCC from non-
[14]
malignant liver diseases , tissue biopsy remains the most dependable option for diagnostic purposes as well
as for recognizing the molecular changes that characterize the tumor. However, tissue biopsy is invasive and
associated with potential risks for the patients, it cannot be repeated and cannot be performed on patients
with unresectable advanced HCC.

In recent years, liquid biopsy has become a valid alternative to overcome the above mentioned limitations.
It is only modestly or not invasive at all and it offers the possibility of carrying out repeated tests over
time. Moreover, it can be used for an early detection of tumors, for monitoring its growth dynamics, for
evaluating the efficacy of treatments and for spotting tumor genetic heterogeneity and identifying mutations
responsible for acquired resistance, becoming a highly promising approach for the clinical management of
cancer patients. Liquid biopsy is the sampling and analysis of biological samples, such as blood, urine, saliva
or stool, where nucleic acids originating from all or part of body districts can be found. In the presence of
cancer, its derived materials, such as circulating tumor cells, cell-free tumor DNA (ctDNA) and microvesicles
containing mRNAs, microRNAs (miRNAs) and proteins, are present in peripheral blood or other body
fluids and can be measured through the use of specific tests [Figure 1]. This review is focused on ctDNA and
circulating non coding RNAs, like miRNAs and long non-coding RNAs (lncRNAs), as potential biomarkers
of HCC for early diagnosis, monitoring patients’ follow-up and assessing response to treatments.

ctDNA
The presence of free circulating DNA in serum/plasma has been used to reveal tumor-associated biomarkers,
such as the increased abundance of cell-free DNA (cfDNA) in cancer patients or the presence of specific
genetic or epigenetic alterations, which have been discovered in numerous types of cancer including HCC.
Several studies have indeed proposed the cfDNA as a source of HCC biomarkers in diagnostic, prognostic or
predictive clinical settings [Table 1].

cfDNA as biomarkers in plasma or serum in HCC
The level of plasma cfDNA was found significantly increased in patients affected by HCC, compared to
individuals with liver fibrosis. A model that included this parameter together with patient age and AFP levels