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Liu et al. Novel predictive and prognostic strategies of HBV-related HCC

for HBsAg and anti-hepatitis C virus (1.55% and genesis, inflammatory microenvironment plays an
[5]
1.30%). Besides, HBV infection is also responsible important role via facilitating the generation of viral and
for the increasing trend of HCC in western countries host genetic mutation and also providing selective
because of the travel and immigration of HBV infected pressure. Therefore, the characteristics of the
[6]
populations. Most HCC patients are diagnosed at microenvironment in different evolutionary phases and
advanced stage and cannot accept resection operation in different populations can be used to stratify HBV-
[7]
or liver transplantation. Approximately 70% patients infected individuals with different risk of developing
that have curative hepatectomy will relapse within HCC. Although inflammatory microenvironment is a
5 years. Both the narrow therapeutic window and complex system, it can be elucidated in two aspects:
[8]
the high recurrence rate highlight the importance of HBV itself and immune imbalance.
developing more rigorous surveillance and more active
prevention for chronic HBV infected subjects with high HBV
HCC risk, and tailoring more suitable treatment options Despite the high incidence of HCC in HBV-infected
for HCC patients, which depend on continuously population, only small percentages of chronic hepatitis
discovering promising biomarkers as well as developing B (CHB) patients develop HCC. HBV variables can
carcinogenesis theory for the specific prophylaxis.
serve as clues to identify distinctive outcomes of HBV-
infected populations, and to guide the personalized
Cancer Evo-Dev is a novel scientific theory describing preventive medication accordingly.
[9]
the mechanism of HBV-induced hepatocarcinogenesis.
The central aspects of its framework are as follows.
Carcinogenesis is an evolutionary process under HBV replication
the microenvironment of chronic non-resolving The level of HBV replication directly reflects the
inflammation. This microenvironment is characterized selective stress from the inflammatory environment,
by immune imbalance due to the interaction between which can influence the evolution of HCC as well.
the genetic predisposition of immune/proinflammatory Currently, HBV DNA load is regularly applied in clinic
molecules and HBV infection. Cytidine deaminases as an indicator of initiating antiviral treatment. It has
and their analogous are persistently activated by been demonstrated by various studies that HBV DNA
[21-23]
proinflammatory factors and subsequently induced load increases the risk of HCC in CHB patients.
mutations both in host and viral genomes. Mutant cells High level of HBV DNA load either in serum or liver
are mostly eliminated by selective pressures. Only tissue can also predict poor postoperative prognosis
[24]
a small proportion can survive in the inflammatory in HCC. Hepatitis B e antigen (HBeAg), encoded
microenvironment because the somatic mutations by HBV precore region, is another marker for active
alter signaling pathways. Those surviving clones replication of HBV. HBeAg positivity has been proved
[25]
usually share some characteristics of stem cells and to be associated with an increased risk of HCC.
gradually retro-differentiate into cancer initialing cells. However, due to HBeAg seroconversion during the
natural course of HBV infection, HBeAg expression
This theory was presented based on recent outcomes is not usually high in HCC patients, explaining the
of HBV-related carcinogenesis researches, mainly reasons that HBeAg positivity is not significantly
including molecular epidemiological studies, cancer associated with an increased risk of HCC in some
genomic mutation analyses, and signaling transduction case-control studies. [14] Thus, HBV DNA load should
researches. [10-20] Those breakthroughs not only be a more reliable indicator in the prediction of HCC.
improved the understanding of cancer evolution
from different aspects but also discovered many HBV genotypes
novel biomarkers and therapeutic targets. Therefore, According to a sequence divergence of no less than 8%
this theory can provide an evolutionary insight of in whole viral genome, HBV can be classified into eight
predicting HCC risk and developing more reasonable genotypes A to H, which can be further classified into
predictive and prognostic biomarkers and therapeutic sub-genotypes if the sequence divergence is between
targets. Here, we summarize the important novel viral, 4% and 8%. [26] Variant genotypes are distributed
inflammatory, genetic, and protein biomarkers of HCC unevenly around the world, and the predominant one
occurrence and prognosis and evaluate them through in mainland China is genotype C (68.3%), followed
the lens of Evo-Dev theory. by genotype B (25.5%). [27] Under selection pressure
from inflammatory microenvironment, the fates of
EVALUATING THE MICROENVIRONMENT different genotypes/sub-genotypes are distinct in a
OF CANCER EVOLUTION given population. Genotype C HBV infection is an
independent risk factor for HCC development. [16,21,28,29]
In the evolution process of HBV-induced hepatocarcino- Meanwhile, genotype B HBV infection was associated

332 Hepatoma Research ¦ Volume 2 ¦ December 23, 2016