Genomics of HCC in the Hispanic population of Texas

项目总结 在美国，肝细胞癌的发病率和死亡率正在迅速上升， 在南得克萨斯州的拉美裔美国人中发现了最高的比率。我们报告了肝硬变的患病率， 德克萨斯州南部拉美裔美国人患肝癌的主要风险因素是全国平均水平的4倍，并已确定 中心性肥胖和糖尿病为主要危险因素。肥胖和糖尿病在肝硬变中的作用 德克萨斯州南部的拉美裔人可能是非酒精性肝癌高发的原因之一 该人群中的脂肪性肝炎(NASH)。在这些人口中，NASH的负担比 预计，包括儿童在内的近20%的人口受到影响。为了应对这种增长的规模 健康差距问题，至关重要的是确定哪些人是肝癌的高危人群，谁将受益于 监测和预防战略。肝癌是一种遗传异质性疾病，是一种特殊的体细胞疾病。 突变图谱与不同的病因有关。西班牙裔种族和纳什病因学至关重要 在肝细胞癌基因组研究中的代表性不足。因此，有必要对NASH-的分子特征进行研究。 与拉美裔人相关的肝癌，以确定生物标记物和靶向治疗开发的机会。 因为已经在肝癌患者的循环细胞游离DNA(CfDNA)中检测到肝癌体细胞突变 但在有肝细胞癌前病变的患者中也是如此，例如肝硬化，其中一个机会是在cfDNA中检测， 对选定的体细胞突变进行肝癌风险评估和早期检测。我们假设这个肿瘤 德克萨斯州南部拉美裔人肝细胞癌的基因组图谱代表了潜在的肝病和 影响这一人群的环境因素以及选定的肝癌体细胞突变可以在 在肝细胞癌早期或诊断前血浆cfDNA，因此可用于肝细胞癌风险评估 以及及早发现。在目标1中，我们将确定NASH相关肝癌的肿瘤基因组图谱。 在南得克萨斯州的西班牙裔，并确定(如果有)这一人群中独特的肝癌特征。在目标2中，我们将 定制设计靶向测序面板，以高灵敏度检测最常见的肝癌体细胞 NASH相关肝细胞癌患者血浆cfDNA中发现AIM 1基因突变。在《目标3》中，我们将 确定AIM 2中确定并应用于cfDNA的基于突变的模型在肝癌风险中的实用性 使用两个以人口为基础的大型拉美裔队列预测南得克萨斯州的拉美裔。这个项目是 由广泛的初步数据、独特的资源和强大的多学科研究团队提供支持。会的 代表了与NASH、糖尿病和肥胖症相关的最大规模的肝细胞癌基因组研究 尤其是受这些慢性病影响的人群。项目影响和翻译目标为：1) 为了服务于南得克萨斯州的拉美裔人口，这一人群在健康和医疗保健方面存在差距，而且 糖尿病、肥胖症、NASH和肝癌的发病率；以及2)开发新的测试方法，以在这一人群中识别受试者 并制定有效的监测和预防策略，提高存活率。

PROJECT SUMMARY The incidence and mortality rates of hepatocellular carcinoma (HCC) is rapidly increasing in the United States, with the highest rates found among Hispanics in South Texas. We reported that the prevalence of cirrhosis, the main risk factor for HCC, in Hispanics in South Texas is 4-times higher than the national average and identified central obesity and diabetes as the main risk factors. The role of obesity and diabetes in liver cirrhosis in Hispanics in South Texas likely contributes to the high prevalence of HCC associated with non-alcoholic steatohepatitis (NASH) in this population. The burden of NASH in this population is more substantial than predicted, affecting close to 20% of the population including children. To address the magnitude of this growing health-disparity problem, it is critically important to identify those at high risk for HCC who would benefit from surveillance and prevention strategies. HCC is a genetically heterogeneous disease and specific somatic mutations profiles are associated with different etiologies. Hispanic ethnicity and NASH etiology are critically underrepresented in HCC genomic studies. Therefore, there is a need for molecular characterization of NASH- associated HCC in Hispanics, to identify opportunities for biomarker and targeted therapy development. Because HCC somatic mutations have been detected in circulating cell free DNA (cfDNA) in patients with HCC but also in patients with pre-HCC conditions such as cirrhosis, one such opportunity is the detection in cfDNA, of selected somatic mutations for HCC risk assessment and early detection. We hypothesize that the tumor genomic landscape of HCC in Hispanics in South Texas is representative of the underlying liver diseases and environmental factors affecting this population and that selected HCC somatic mutations can be detected in plasma cfDNA at early HCC stage or prior to diagnosis and could therefore have utility in HCC risk assessment and early detection. In Aim 1, we will determine the tumor genomic landscape of NASH-associated HCC in Hispanics in South Texas and identify (if any) unique features of HCC in this population. In Aim 2, we will custom-design a targeted sequencing panel to detect with high sensitivity the most common HCC somatic mutations identified in Aim 1, in plasma cfDNA of patients with NASH-associated HCC. In Aim 3, we will determine the utility of the mutation-based model identified in Aim 2 and applied to cfDNA, in HCC risk prediction in Hispanics in South Texas using two large population-based Hispanic cohorts. This project is supported by extensive preliminary data, unique resources and a strong multidisciplinary research team. It will represent the largest genomic study of HCC associated with NASH, diabetes and obesity in an underserved population particularly affected by these chronic diseases. The project impact and translational goals are: 1) to serve the Hispanic population in South Texas, a population with health and healthcare disparities and high rates of diabetes, obesity, NASH and HCC; and 2) to develop new tests to identify, in this population, subjects at high risk for HCC and institute effective surveillance and prevention strategies, improving survival.