# gamma-OHPdG as a prognostic biomarker of HCC recurrence and its prevention

> **NIH NIH U01** · GEORGETOWN UNIVERSITY · 2021 · $327,696

## Abstract

Hepatocellular carcinoma (HCC) is the third leading cause of cancer–related deaths worldwide,
mainly because of its poor prognosis. A valid and reliable mechanism-based prognostic
biomarker is urgently needed. γ-Hydroxy-1,N2-propanodeoxyguanosine (γ-OHPdG) is an
endogenous mutagenic DNA adduct derived from lipid peroxidation (LPO). We studied the
relationship between hepatic γ-OHPdG and hepatocarcinogenesis in three animal models and
the potential of γ-OHPdG to be used as a prognostic biomarker for recurrence in HCC patients
after surgical resection. Tumor bioassays were conducted in Xeroderma pigmentosum group A
knockout mice (Xpa-/-), diethylnitrosamine (DEN)-injected mice, and Long-Evans Cinnamon
(LEC) rats, and all are prone to HCC development. We found that the increased γ-OHPdG
levels in liver DNA correlated with HCC development in all three animal models. Furthermore,
Theaphenon E treatment significantly decreased γ-OHPdG levels in the liver DNA of Xpa-/-
mice, and this decrease was closely associated with its remarkable effect to reduce HCC
incidence (from 100% to 14%). Theaphenon E also effectively inhibited HCC development in
DEN-injected mice. Using two independent sets of clinical samples from 90 and 45 HCC
patients, our studies demonstrated that higher levels of γ-OHPdG in HCC biopsy specimens,
detected by immunohistochemical staining , are strongly associated with low survival
(p<0.0001) and low recurrence-free survival (p=0.007), respectively. These results support γ-
OHPdG as a promising biologically relevant biomarker for predicting the risk of HCC and its
recurrence. In this proposal, we propose in Aim 1 to extend these exciting findings to include a
larger patient population to further address questions on γ-OHPdG’s relationships with (1) the
underlying etiology of HCC, e.g. HBV, HCV, alcoholic liver disease, and non-alcoholic
steatohepatitis (NASH) and (2) clinical predictors for aggressiveness, e.g. differentiation, HCC
stage, vascular invasion, and extra-hepatic metastasis. We also want to compare its levels with
those of the adjacent non-tumorous tissues and to examine the tumor mutation load. In Aims 2
and 3, we will develop a non-invasive method for detecting γ-OHPdG in human urine. Our
hypothesis is that the adduct levels in urine reflect those in liver DNA. In Aim 4, we will conduct
an intervention trial with Polyphenon E, an FDA approved equivalent of Theaphenon E, to
prevent HCC recurrence in high risk patients identified with high liver γ-OHPdG. Our long-term
goal is to develop γ-OHPdG as a prognostic biomarker for HCC and its recurrence for
intervention trials.

## Key facts

- **NIH application ID:** 10246882
- **Project number:** 5U01CA220477-04
- **Recipient organization:** GEORGETOWN UNIVERSITY
- **Principal Investigator:** FUNG-LUNG CHUNG
- **Activity code:** U01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $327,696
- **Award type:** 5
- **Project period:** 2018-09-10 → 2023-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10246882

## Citation

> US National Institutes of Health, RePORTER application 10246882, gamma-OHPdG as a prognostic biomarker of HCC recurrence and its prevention (5U01CA220477-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10246882. Licensed CC0.

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