Southern Liver Health Cohort

项目摘要/摘要 原发性肝癌，其中绝大多数是肝细胞癌(肝细胞癌)是为数不多的 在美国的发病率不断上升。自1980年以来，肝癌的发病率增加了两倍，这一点尤其令人担忧 肝细胞癌的中位生存期不到两年。发病率上升幅度最大的是南部 在农村各州和少数民族中。虽然肝细胞癌的患病率与病毒性肝炎的高发病率平行 在过去的几十年里，最近非酒精性脂肪性肝病(NAFLD)和 近年来，其进展为伴有纤维化和硬化的非酒精性脂肪性肝炎(NASH)，助长了肝细胞癌的发生。 然而，这些因素本身并不能解释肝细胞癌进展过程中存在显著的地区和种族差异。一 未被充分研究但潜在的潜在肝癌风险因素，其患病率不断上升，对 少数民族，是暴露在环境污染物中的。这些污染物降解缓慢，因此 坚持在环境中，为人类暴露提供稳定的外源来源。有毒金属(类)S等 镉和砷被归类为可能的致癌物质，来自小鼠模型的新数据表明 这种暴露与肝脏脂肪变性、肝硬变和肝癌有关。全氟烷基和多氟烷基 人类接触到的物质(PFAS)与肥胖和NASH有关。此外，不断涌现的证据 表明这些环境暴露可以诱导表观遗传改变，这可能会促进不利的 对肝脏的影响，但我们缺乏纵向的人体数据。这些数据强调了对纵向人类的需求 评估这些污染物是否以及如何影响肝细胞癌风险的数据。为了解决这些知识差距，以及 作为对RFA-CA-20-049的响应，我们建议南方肝脏健康研究，这是一项纵向队列研究，包括两项 由16,000名年龄在40岁及以上的男性和女性组成的子队列，分布在美国东南部的两个州，北部 卡罗莱纳州和佐治亚州。我们将测试最重要的假设，即镉单独或与其他物质混合 有毒金属和PFAS增加了从NAFLD进展到肝纤维化和肝细胞癌的风险。这群人将 从社区诊所招聘，包括联邦合格的卫生中心和大学卫生系统 杜克大学、北卡罗来纳大学教堂山分校和埃默里大学的初级保健中心和肝病项目。子队列I将包括 1万名其他方面健康的成年人将被跟踪1-5年，预计约800例纤维化病例， 包括肝硬变在内的疾病将会发展，第二组将包括6,000例晚期纤维化病例，预计约为750例 肝细胞癌病例将会发展。我们将在队列中嵌套病例对照研究，评估 环境暴露和肝细胞癌发病率，并确定对污染物有反应的表观遗传标记 预测进展为肝细胞癌。影响：这将是第一次大规模的纵向确定联系的努力 在居住和种族多元化的环境污染物、肝病和癌症之间 人口。此外，我们将创建一个数据和标本存储库，为研究社区提供 拥有研究肝细胞癌和其他癌症的宝贵资源。

PROJECT SUMMARY/ABSTRACT Primary liver cancer, the vast majority of which is hepatocellular carcinoma (HCC) is one of the few cancers with increasing incidence in the US. Incidence of HCC has tripled since 1980, which is particularly worrisome given that HCC confers a median survival of less than two years. The steepest increases in incidence are in Southern rural states and among ethnic minorities. While the prevalence of HCC had paralleled high rates of viral hepatitis in the last several decades, recent increases in the prevalence of nonalcoholic fatty liver disease (NAFLD) and its progression to nonalcoholic steatohepatitis (NASH) with fibrosis and cirrhosis, has fueled HCC in recent years. Yet, these factors alone do not explain the substantial regional and ethnic variation in HCC progression. One understudied but potentially potent HCC risk factor with increasing prevalence that disproportionately affects ethnic minorities, is exposure to environmental contaminants. These contaminants degrade slowly and therefore persist in the environment, providing a stable exogenous source for human exposure. Toxic metal(oid)s such as cadmium and arsenic are classified as probable carcinogens, and emerging data from murine models suggest that exposure is associated with hepatic steatosis, cirrhosis and liver cancer. Per- and poly-fluoroalkyl substances (PFAS) exposure in humans is associated with obesity and NASH. Further, emerging evidence indicates that these environmental exposures can induce epigenetic alterations that may promote adverse effects on the liver, but we lack longitudinal human data. These data underscore the need for longitudinal human data to assess whether and how these contaminants impact HCC risk. To address these knowledge gaps, and in response to RFA-CA-20-049, we propose the Southern Liver Health Study, a longitudinal cohort study of two sub-cohorts comprising 16,000 males and females aged 40 years and older in two Southeastern states, North Carolina and Georgia. We will test the overarching hypothesis that cadmium alone or in a mixture with other toxic metals and PFAS increases the risk of progression from NAFLD to liver fibrosis and HCC. The cohort will be recruited from community clinics including Federally Qualified Health Centers and University Health Systems’ Primary Care Centers and Hepatology programs at Duke, UNC Chapel Hill and Emory. Sub-cohort I will comprise 10,000 otherwise healthy adults who will be followed for 1–5 years, anticipating that ~800 fibrosis cases, including cirrhosis, will develop, and sub-cohort II will comprise 6,000 advanced fibrosis cases, anticipating ~750 HCC cases will develop. We will nest case-control studies within the cohorts, evaluate associations between environmental exposures and HCC incidence, and identify epigenetic marks responsive to contaminants that predict progression to HCC. Impact: This will be the first large-scale effort to longitudinally determine the link between environmental contaminants, liver disease and cancer in a residentially and ethnically diverse population. Additionally, we will create a data and specimen repository that will provide the research community with an invaluable resource to study HCC and other cancers.