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Page 4 of 22 Nevola et al. Hepatoma Res 2018;4:55 I http://dx.doi.org/10.20517/2394-5079.2018.38

risk of developing HCC has been reported to be 6-, 5- and 4-fold higher in the case of concomitant use of
[21]
alcohol, tobacco and in the presence of obesity, respectively .

The presence of HBV coinfection with HIV or HDV or HCV causes a more rapid progression of liver disease
and a significant higher occurrence of HCC even in the early stages of the disease [22,23] .

HBV genotype appears to significantly influence the appearance of HCC. In particular, it has been reported
that HBV genotype C, which has a high prevalence in Southeast Asia, is associated with a higher risk of
HCC compared to other genotypes [24,25] . It has been shown that HBV genotype C most frequently causes
double helix breaks in the host genome, induces a greater stress of the endoplasmic reticulum through
the accumulation of ROS and causes a greater number of chromosomal rearrangements that can promote
[26]
carcinogenesis as better described below .
As mentioned above, high viral loads, as well as a seropositive status of HBe antigen (HBeAg) are associated
[14]
with a higher risk of developing HCC . It has been reported that HBeAg seropositive patients has a relative
[27]
risk of HCC of 60.2 compared to 9.6 of those seronegative . It has also been shown that high levels of HBV-
[28]
DNA are closely linked to a high probability of developing HCC .
A genetic predisposition to the development of HCC during HBV infection has been reported among South-
Asians. Single nucleotide polymorphisms (SNPs) at the level of several genes, e.g. DCL1, TGF-β1, STAT4,
TPTE2, CTL-4, MDM2 have been associated with the development of HCC [12,29-33] . It is unknown, however,
if these data may be extended to other ethnicities.

Pathogenic mechanisms of HBV-related HCC
HBV can cause the onset of HCC through direct and indirect mechanisms. The direct carcinogenic effect of
HBV derives from its ability to integrate its own genome into that of the host, altering chromosomal stability
and triggering various oncogenic mechanisms. In the early stages of the natural history of infection, HBV-
[34]
DNA is converted into a covalently closed circular DNA form (cccDNA) that allows the virus to persist
[12]
in the infected cell nucleus and acts as a reserve for viral genome replication . Although viral integration
is more likely to occur randomly, whenever it occurs at the level of specific sites in the host genome, which
are either close to the genes involved in cell cycle regulation and proliferation or those involved in cell
survival mechanisms, can allow the clonal expansion of cells [35,36] . This mechanism is also responsible for the
constant expression of viral oncogenic proteins such as HBx or preS/S polypeptides, which over time may
[12]
lead to alterations in the control of cell transcription and proliferation . The fact that such integration is
more commonly seen in cancer tissue than in adjacent liver tissue (86.4% and 30.7%, respectively) seems to
[37]
be an evidence of the central role played by viral genome integration in the development of HCC . In this
context, the transcription of a chimeric gene (viral/human) called HBxLINE1 has recently been identified
[38]
and has been found in about a quarter of patients with HCC and associated with a worse prognosis .
In addition to the integration mechanisms of the viral genome, specific mutations in the X regions, pre-core,
core-promoter and pre-S may increase the risk of developing HCC [39,40] . Among the most frequent mutations
at the nuclear promoter level, the double mutation A1762T/G1764A is closely related to the probability of
developing HCC. The presence of this mutation may represent a potentially risk-predictive biomarker for
[41]
HCC as its presence may be evident many years before the development of HCC . Several other potentially
oncogenic mutations have been identified in the pre-S region. The combination of pre-S C1653T, C1653T
+ T1753V mutations and the aforementioned A1762T/G1764A have a specificity greater than 80% in the
[42]
prediction of HCC development . HBV-infected patients with mutations in the pre-S region have a 3.8-
fold higher risk of developing HCC than non-mutated virus infection. These mutations are present in about
60% of cases of HCC and may alter the protein expression of the viral envelope. The accumulation of surface