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

with the development of HCC in young patients using interferon and nucleoside analogues (NAs)
(< 50 years old). [30] Our study further revealed that significantly reduced HCC occurrence (13.90/1,000 vs.
genotype B2 HBV infection was related to HCC 7.70/1,000 person-years, P = 0.005). [36] Furthermore,
recurrence, and that HBV genotype C2 HBV was proved by a cohort study and randomized clinical
predominant in HCC patients, which was related trial, treatment with NAs can also significantly reduce
to its high prevalence. [31] As the HBV genotype is the risk of early recurrence (hazard ratios, 0.41; P <
usually identified through a complex procedure that 0.001). [13] However, levels of those protective effects
includes extracting HBV DNA, polymerase chain are distinct among HBV-infected subjects with different
reaction, sequencing, and phylogenetic analysis, the viral mutations. Antiviral treatment with NAs cannot
wide application of HBV genotype/subgenotype for reduce HCC risk in patients without A1762T/G1764A
preliminary screening in community is limited. or C1653T and in those with T1753V. [36] The protective
function of antiviral treatments for postoperative
HBV mutations recurrence cannot be observed in the HCC patients
In the process of HBV-HCC evolution, one of the most expressing carboxylic acid-terminal truncated HBV X
prominent molecular events is the generation of HBV protein (Ct-HBx) in their liver remnants. [13]
mutation, especially mutations in the preS region and
basic core promoter (BCP) region of HBV genome. Immune imbalance
Due to lack of proof reading capacity, HBV genome Immune imbalance is responsible for the maintenance
has a higher mutation rate than other DNA viruses. of chronic non-resolving inflammation and
Moreover, inflammatory factors induced by HBV subsequently provides a fertile microenvironment for
infection can activate the expression of apolioprotein cancer evolution. Immune imbalance can be reflected
B mRNA editing enzyme catalytic polypeptides by the proportion shift of immune cells, abnormal
(APOBECs). HBV genome can be degraded and activation of inflammatory pathways, and genetic
edited by APOBECs. [32] Most HBV mutants are predisposition of inflammatory molecules, which can
cleared by host immune system, and only those that serve as biomarkers for HCC prediction and prognosis.
gained the ability to escape immune eradication
survived. The mutant viruses, in return, keep on Immune cells
stimulating the immune system and maintain the The liver is enriched with innate immune cells such as
inflammatory microenvironment. The HBV mutations macrophages and natural killer (NK) cells, as well as
reflect, to some extent, the selection pressure of host adaptive immune cells such as CD8 cytotoxic T cells,
+
immune system and serve as risk factors of HCC. CD4 T helper cells and B cells, playing an important
+
role not only in host defenses against invading
Our recent study of HBV mother-to-child transmission microorganisms and tumor transformation, but also in
revealed that mutated viruses lost their advantages liver injury and repair. Their presence or enrichment can
in infecting infants, whereas the wild-type HBV had be seen as predictive or prognostic factors for HCC.
advantage of infecting newborn’s hepatocytes, CD8 T in liver tissues, for example, is the protective
+
interestingly, the HCC-risk HBV mutations was being factor, while the enrichment of M2 macrophages and
gradually selected since the establishment of chronic T helper 17 cells (Th17) as well as the imbalance
[10]
infection. Mutations in HBV the preS region (including between CD8 T cells and regulatory T (Treg) cells or
+
A2962G, A2964C, C3116T, C7A, T105C, and preS between Th1 and Th2 are the risk factors of HCC. [37]
start codon mutation) and mutations in the BCP region Immune cells that infiltrated into HCC tissues function
(including C1653T, T1753V, and A1762T/G1764A) distinctly on HCC prognosis. Intratumoral natural
+
were independently associated with an increased risk killer cells and CD8 T cells indicate good prognosis,
of HCC. [11,15,21,33] Mutations in combination (combo while intratumoral Treg cells, neutrophils, and M2
mutations) can enhance the validity of predicting the macrophages indicate poor prognosis. [37]
occurrence of HCC. [21,33,34] HBV combo mutations
of C1653T, T1753V, and A1762T/G1764A increase Inflammatory pathways
the validity of HCC prediction compared with single The abnormal alteration of inflammatory pathways
HBV mutation. [21] The HBV mutations can improve the can be reflected by hallmark cytokines. Biomarkers
sensitivity and specificity of HCC prediction model based indicating the abnormal activation of inflammatory
on age, gender, cirrhosis and HBV DNA loads. [21,25,35] pathways can also predict the occurrence and
recurrence of HCC. [38,39] For example, Wnt/β-catenin
The carcinogenic effects of HBV can be blocked signaling pathway plays an important role in
by antiviral treatments. In our prospective hospital- inflammation-induced carcinogenesis via regulating the
based cohort study, antiviral treatment against HBV expression of cytokine-induced human inducible nitric

Hepatoma Research ¦ Volume 2 ¦ December 23, 2016 333