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Fu et al. Hepatoma Res 2018;4:39 I http://dx.doi.org/10.20517/2394-5079.2018.29 Page 3 of 8

[57]
ablation (RFA) . Since cancer is a genetic disease, we think that mutagenic DNA adducts that arise from
oxidative stress have the potential to serve as more direct and precise biomarkers to predict HCC risk and
recurrence. A major oxidative stress and promutagenic DNA adduct, 8-oxo-7, 8-dihydro-2’-deoxyguanosine
(8-oxo-dG), was found to be increased during hepatocarcinognesis. It suggests a role of mutagenic DNA le-
sions in HCC formation [58,59] . In an HCV/HCC clinical trial, the result supports the hypothesis that HCV in-
duces inflammation that causes oxidative DNA damage (increase of 8-oxo-dG, a DNA lesion), and promotes
hepatocarcinogenesis.

LPO induced DNA adducts, including various propano- and etheno- adducts, have been investigated
as potential lead markers for various types of inflammatory/oxidative stress cancer-prone diseases (e.g.,
chronic pancreatitis, Crohn`s disease, ulcerative colitis, alcohol related hepatitis, H. pylori infection) and
2
cancer initiation/promotion [60,61] . It is also known that the propano DNA adducts [e.g., γ-hydroxy-1,N -
propanodeoxyguanosine (γ-OHPdG)] arisen from lipid peroxidation are mutagenic and associated with liver
[62]
cancinogenesis . The levels of propano DNA lesions are the balance of oxidative stress induced LPO and
DNA repair. Nucleotide excision repair (NER) pathway is mainly responsible for repairing these bulky DNA
adducts [43,63,64] . Patients with HBV may exhibit inefficiency of removing bulky DNA adducts because HBx
protein has been shown to inhibit NER pathways through suppressing XPB and XPD helicases [transcription
[65]
factor IIH (TFIIH)] . We reason that DNA adducts possibly play a role of causing mutations by HBV, but
further testing should be done to prove this hypothesis.

[66]
γ-OHPdG is an endogenous product of acrolein, a reactive aldehyde generated by LPO . γ-OHPdG is
known to cause G to T and G to A mutations that may involve critical genes such as p53 [67-70] . Our recent
studies demonstrated an association of the levels of γ-OHPdG with HCC development in a NER deficient
mouse model with spontaneous HCC development. It is also found that antioxidants can suppress γ-OHPdG
and prevent liver cancer significantly [71,72] . Further analysis found that GC>TA mutation is the dominant al-
teration, accounting for approximately 90% of mutations. The high GC>TA mutation frequency implies that
γ-OHPdG may play a role in the mutagenesis of HCC development [71,72] . Understanding the role of DNA ad-
ducts of lipid peroxidation and the repair pathways involved may shed light onto mutagenesis during HCC
[73]
development, and this knowledge will help us to find a way to its prevention . To our knowledge, there is
still no clinical data regarding LPO-derived DNA adducts as a predictive biomarker for HCC risk, we hope
the ongoing interventional multi-center clinical trial “defined green tea catechin extract in preventing liver
cancer in patients with cirrhosis (NCT03278925)” will shed some light on γ-OHPdG as a biomarker for liver
carcinogenesis.

Thanks to recent advances in imaging modalities and the prevalence of a surveillance method for HCC, an
increasing proportion of patients now receive local ablation therapy or curable resection. However, the high
annual recurrence rate (approximately 20%) is still a huge hurdle before achieving long-term disease-free
[74]
survival . Neoadjuvant and adjuvant therapy for resectable HCC is still a difficult challenge. There are two
major postoperative recurrence mechanisms: de novo carcinogenesis (usually late recurrence) and metastatic
[75]
recurrence (usually occurs within one year and is related to intrahepatic metastasis) . Precise prevention
[76]
strategies are needed to target these mechanisms . Three major strategies have been developed to address
[77]
this issue . The first one is a virus eradication method using interferon. But this method is not going to
[78]
rescue the hepatocytes which have been damaged by hepatitis virus . The second strategy is the use of an-
ticancer drugs. Difficulties have been reported in the STROM trial (sorafenib as adjuvant treatment in the
[79]
prevention of recurrence of hepatocellular carcinoma) and with the use of UFT (Tegafur-uracil) . The last
strategy is to induce differentiation of liver cancer cells. For example, using Pertinoin, an acyclic retinoid
which can induce apoptosis and differentiation of cancer cells. This method has shown promising survival
beneficial effects in a clinical phase II trial. Other than these strategies, branched chain amino-acid supple-
[80]
mentation, vitamin K2 and acyclic retinoid have also been examined . The reality is that no chemopreven-