An endogenous DNA adduct as a prognostic biomarker for hepatocarcinogenesis and its prevention by Theaphenon E in mice

Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related deaths worldwide, mainly because of its poor prognosis. A valid mechanism-based prognostic biomarker is urgently needed. γ-hydroxy-1,N2-propanodeoxyguanosine (γ-OHPdG) is an endogenously formed mutagenic DNA adduct derived from lipid peroxidation (LPO). We examined the relationship of γ-OHPdG with hepatocarcinogenesis in two animal models and its potential role as a prognostic biomarker for recurrence in HCC patients. Bioassays were conducted in the Xeroderma pigmentosum group A knockout mice (Xpa-/-), and the diethylnitrosamine (DEN)-injected mice, both prone to HCC development. γ-OHPdG levels in the livers of these animals were determined. The effects of antioxidant treatments on γ-OHPdG and hepatocarcinogenesis were examined. Using two independent sets of HCC specimens from patients, we examined the relationship between γ-OHPdG and survival or recurrence-free survival. γ-OHPdG levels in liver DNA showed an age-dependent increase and consistently correlated with HCC development in all three animal models. Theaphenon E treatment significantly decreased γ-OHPdG levels in the liver DNA of Xpa-/- mice, and remarkably reduced HCC incidence in these mice to 14% from 100% in the controls. It also effectively inhibited HCC development in the DEN-injected mice. Using clinical samples from two groups of patients, our study revealed that higher levels of γ-OHPdG are strongly associated with low survival (p < 0.0001) and low recurrence-free survival (p = 0.007), respectively. Conclusion: These results support γ-OHPdG as a mechanism-based biologically relevant biomarker for predicting the risk of HCC and its recurrence. Genetic and epigenetic alterations in oncogenes and tumor-suppressor genes are crucial for carcinogenesis (1, 2). Somatic mutations may arise from DNA lesions that are not repaired. During lifetime, human genome will host a wide-spectrum of mutagenic DNA lesions, induced by chemical carcinogens, viruses, and reactive oxygen and nitrogen species. This is believed to be the case for human liver as it is a major detoxifying organ that is exposed to a large number of risk factors (3-5). This article is protected by copyright. All rights reserved.