Epigenetic Heterogeneity as a Driver of Liver Disease and Cancer

表观遗传异质性是肝病和癌症的驱动因素

• 批准号: 10165422
• 负责人: Chen Liu
• 金额: $ 50.62万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-15 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10165422
• 关键词: AFP gene; Alcohol abuse; Alcohol dependence; Alcohols; Animal Model; Area; Automobile Driving; Cancer Etiology; Cell Culture Techniques; Cessation of life; Chronic; Cirrhosis; Clinical; DNA; DNA Methylation; DNA Modification Methylases; Data; Detection; Development; Disease; Disease Progression; Early Diagnosis; Enhancers; Environment; Environmental Exposure; Epigenetic Process; Etiology; Event; Evolution; Excision; Experimental Models; Family; Foundations; Frequencies; Future; Genes; Genetic; Genetic Transcription; Genome Stability; Geography; Growth; Hand; Hepatitis C; Hepatitis C virus; Hepatocarcinogenesis; Heterogeneity; Human; Individual; Laboratories; Lesion; Liver; Liver Cirrhosis; Liver diseases; Liver parenchyma; Malignant Neoplasms; Malignant neoplasm of liver; Maps; Mediating; Methods; Methylation; Mus; Mutation; Nodule; Pathologic; Pathologic Processes; Patients; Pattern; Plasma; Primary carcinoma of the liver cells; Publishing; Regulation; Regulatory Element; Resolution; Resources; Risk; Role; Sampling; System; Testing; Time; Tissues; United States; Viral; Work; Xenograft Model; alcohol abstinence; base; blood-based biomarker; carcinogenesis; cell free DNA; cell growth; chronic infection; early detection biomarkers; environmental change; epigenetic marker; epigenome; genome-wide; genome-wide analysis; liver injury; liver transplantation; mortality; novel; novel therapeutics; premalignant; prevent; promoter; recreational drug abuse; regenerative; screening; targeted treatment; transcriptome sequencing; tumor; tumor heterogeneity; tumor progression; tumorigenesis; unpublished works

Hepatocellular carcinoma (HCC) is among the fastest-growing causes of cancer-related death in the U.S due to a lack of early detection strategies and therapies that target this highly heterogeneous tumor. Alcohol, a frequently abused recreational drug and hepatitis C virus (HCV), which establishes chronic infection, cause liver damage and cirrhosis and dramatically enhance risk for HCC. While great strides have been made in treating HCV infection, most individuals do not know they are infected. Individuals cured of HCV or who break their alcohol addiction remain at long-term risk for HCC. While screening liver cirrhosis patients for HCC clearly reduces mortality, >50% of HCCs are negative for the one blood-based marker available (AFP), emphasizing the dire need for better screens. Thus, it is crucial to gain a complete understanding of the pathological processes driving HCC in order to define those at greatest risk for HCC and develop new therapies to prevent or reverse liver carcinogenesis. While evidence that alcohol and HCV induce genetic changes is limited, we and others have shown that components of the epigenome, particularly DNA methylation (5mC) and DNA hydroxymethylation (5hmC), are profoundly disrupted during liver disease progression. One of the greatest challenges, however, is determining which epigenetic changes are drivers and which represent novel HCC early detection markers. We comprehensively examined genome-wide 5mC/5hmC analyses in HCC to reveal high frequency etiologic- and disease-stage specific changes, and we identified a panel of putative epigenetic drivers that we build on in this proposal. Based on these data, we propose three aims to test the central hypothesis of this application that epigenetic heterogeneity in cirrhosis underpins HCC development and progression. Elucidating the mechanisms underlying this effect is expected to yield novel drivers of HCC and early detection markers. Given that these are epigenetic targets, they also represent clinically targetable drivers. In aim 1 we define epigenetic heterogeneity during carcinogenesis of premalignant liver cirrhosis to HCC and define epigenetic drivers of tumor evolution. In aim 2, building on preliminary and published data identifying epigenetic driver loci and developing novel cell culture and PDX models, we functionally interrogate the role of loci targeted by aberrant 5mC/5hmC in driving HCC. Finally, in aim 3 we identify circulating cell-free DNA methylation signatures that differentiate between patients with cirrhosis and patients with cirrhosis and HCC and study their relationships with tumor heterogeneity. Results from these studies are expected to greatly expand our understanding of how epigenetic changes drive HCC, provide new actionable targets for treatment, and establish the foundations for future studies developing 5mC as an HCC early detection marker.

肝细胞癌 (HCC) 是美国癌症相关死亡增长最快的原因之一 缺乏针对这种高度异质性肿瘤的早期检测策略和治疗方法。酒精，一种 经常滥用的娱乐性药物和丙型肝炎病毒 (HCV) 会造成慢性感染，导致 肝损伤和肝硬化，并显着增加患肝癌的风险。虽然已经取得了巨大进步 在治疗 HCV 感染时，大多数人并不知道自己已被感染。 HCV 治愈者或 戒除酒瘾仍面临罹患肝癌的长期风险。在筛查肝硬化患者时 HCC 明显降低了死亡率，>50% 的 HCC 的一种可用血液标记物 (AFP) 呈阴性， 强调迫切需要更好的屏幕。因此，全面了解这一点至关重要 驱动 HCC 的病理过程，以确定 HCC 风险最大的人群并开发新的 预防或逆转肝癌发生的疗法。虽然有证据表明酒精和丙型肝炎病毒会诱发遗传 变化是有限的，我们和其他人已经证明表观基因组的成分，特别是 DNA 甲基化 (5mC) 和 DNA 羟甲基化 (5hmC) 在肝病期间受到严重破坏 进展。然而，最大的挑战之一是确定哪些表观遗传变化是驱动因素 并代表新的 HCC 早期检测标志物。我们全面检查了全基因组 HCC 中的 5mC/5hmC 分析可揭示高频病因学和疾病阶段的特定变化，我们 确定了我们在此提案中建立的一组假定的表观遗传驱动因素。根据这些数据，我们 提出三个目的来检验该应用的中心假设，即表观遗传异质性 肝硬化是 HCC 发生和进展的基础。阐明这种效应的机制是 预计将产生 HCC 的新驱动因素和早期检测标记物。鉴于这些是表观遗传目标， 它们也代表了临床上可定位的驱动因素。在目标 1 中，我们定义了表观遗传异质性 癌前肝硬化至 HCC 的致癌作用，并定义肿瘤进化的表观遗传驱动因素。瞄准目标 2、基于初步和已发表的数据识别表观遗传驱动基因座并开发新细胞 培养和 PDX 模型中，我们从功能上探讨了异常 5mC/5hmC 所针对的位点在 驾驶肝癌。最后，在目标 3 中，我们确定了区分不同细胞的循环游离 DNA 甲基化特征 肝硬化患者与肝硬化合并肝癌患者之间的关系并研究其与肿瘤的关系 异质性。这些研究的结果预计将大大扩展我们对如何 表观遗传变化驱动 HCC，为治疗提供新的可行目标，并奠定基础 供未来研究开发 5mC 作为 HCC 早期检测标记物。