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

γ-OHPdG 作为 HCC 复发及其预防的预后生物标志物

• 批准号: 10246882
• 负责人: FUNG-LUNG CHUNG
• 金额: $ 32.77万
• 依托单位: GEORGETOWN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-10 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10246882
• 关键词: Acrolein; Address; Aftercare; Alcoholic Liver Diseases; Animal Model; Antioxidants; Binding; Biological; Biological Assay; Biological Markers; Biopsy Specimen; Blood Vessels; Cancer Etiology; Cessation of life; Clinic; Clinical; DNA; DNA Adducts; Development; Diagnosis; Diethylnitrosamine; Epigallocatechin Gallate; Etiology; Excision; Extrahepatic; FDA approved; Formulation; Future; Goals; Healthcare; Hepatic; Hepatitis B Virus; Hepatitis C virus; Hepatocarcinogenesis; Human; Inbred LEC Rats; Incidence; Inflammation; Intervention Trial; Knockout Mice; Lipid Peroxidation; Liver; Malignant Neoplasms; Malignant neoplasm of liver; Measures; Methods; Modeling; Molecular; Mus; Mutation; Neoplasm Metastasis; Nucleotide Excision Repair; Operative Surgical Procedures; Pathway interactions; Patients; Polyphenon E; Polyunsaturated Fatty Acids; Prevention; Primary Malignant Neoplasm of Liver; Primary carcinoma of the liver cells; Prognosis; Prognostic Marker; Recurrence; Resistance; Risk; Role; Sampling; Stains; TP53 gene; Time; Tissues; Urine; Xeroderma Pigmentosum; adduct; base; cancer recurrence; carcinogenesis; chemotherapy; clinical application; clinical predictors; disorder later incidence prevention; early detection biomarkers; high risk; in vivo; liver biopsy; nonalcoholic steatohepatitis; oxidation; patient population; predictive marker; prevent; recruit; tumor; urinary

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.

肝细胞癌 (HCC) 是全球癌症相关死亡的第三大原因， 主要是因为其预后较差。有效且可靠的基于机制的预测 迫切需要生物标志物。 γ-羟基-1,N2-丙脱氧鸟苷 (γ-OHPdG) 是一种 源自脂质过氧化 (LPO) 的内源性诱变 DNA 加合物。我们研究了 三种动物模型中肝脏γ-OHPdG与肝癌发生的关系 γ-OHPdG 作为 HCC 患者复发的预后生物标志物的潜力 手术切除后。在着色性干皮病 A 组中进行肿瘤生物测定 基因敲除小鼠 (Xpa-/-)、注射二乙基亚硝胺 (DEN) 的小鼠和 Long-Evans Cinnamon (LEC) 大鼠，所有这些大鼠都容易发生 HCC。我们发现γ-OHPdG增加 在所有三种动物模型中，肝脏 DNA 水平与 HCC 的发展相关。此外， Theaphenon E 处理显着降低 Xpa-/- 肝脏 DNA 中的 γ-OHPdG 水平 小鼠，这种减少与其显着的减少 HCC 的效果密切相关 发生率（从 100% 到 14%）。 Theaphenon E 还可以有效抑制 HCC 的发展 注射 DEN 的小鼠。使用来自 90 例和 45 例 HCC 的两组独立临床样本 我们的研究表明，HCC 活检标本中的 γ-OHPdG 水平较高， 通过免疫组织化学染色检测，与低存活率密切相关 (p<0.0001) 和低无复发生存率 (p=0.007)。这些结果支持γ- OHPdG 作为一种有前途的生物学相关生物标志物，用于预测 HCC 及其风险 复发。在本提案中，我们在目标 1 中建议扩展这些令人兴奋的发现，以包括 更大的患者群体，以进一步解决 γ-OHPdG 与 (1) 关系的问题 HCC 的潜在病因，例如HBV、HCV、酒精性肝病和非酒精性肝病 脂肪性肝炎 (NASH) 和 (2) 侵袭性的临床预测因子，例如分化、肝癌 分期、血管侵犯和肝外转移。我们还想将其水平与 邻近非肿瘤组织的那些并检查肿瘤突变负荷。目标 2 3、我们将开发一种非侵入性检测人尿液中γ-OHPdG的方法。我们的 假设尿液中的加合物水平反映了肝脏 DNA 中的加合物水平。在目标 4 中，我们将进行 Polyphenon E（FDA 批准的 Theaphenon E 等效物）的一项干预试验 预防肝 γ-OHPdG 高水平高危患者的 HCC 复发。我们的长期 目标是开发 γ-OHPdG 作为 HCC 及其复发的预后生物标志物 干预试验。