Genomics of HCC in the Hispanic population of Texas

项目摘要 肝细胞癌（HCC）的发病率和死亡率在美国迅速增加， 在德克萨斯州南部的西班牙裔中，我们报道了肝硬化的患病率， 在德克萨斯州南部的西班牙裔中，HCC的主要风险因素是全国平均水平的4倍， 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化中的作用 德克萨斯州南部的西班牙裔可能导致与非酒精相关的HCC的高患病率 脂肪性肝炎（NASH）。该人群中NASH的负担比 据预测，这将影响包括儿童在内的近20%的人口。为了解决这一日益增长的 健康差异问题，识别那些有HCC高风险的人， 监测和预防战略。HCC是一种遗传异质性疾病， 突变谱与不同的病因学有关。西班牙裔种族和NASH病因是至关重要的 在HCC基因组研究中代表性不足。因此，需要对NASH的分子表征。 相关的西班牙裔HCC，以确定生物标志物和靶向治疗开发的机会。 由于在HCC患者的循环细胞游离DNA（cfDNA）中检测到HCC体细胞突变， 而且在具有前HCC病症如肝硬化的患者中，一个这样的机会是cfDNA中的检测， 用于HCC风险评估和早期检测的选定体细胞突变。我们假设肿瘤 南德克萨斯州西班牙裔HCC的基因组图谱代表了潜在的肝脏疾病， 影响这一人群的环境因素，并且可以在患者中检测到选定的HCC体细胞突变。 在早期HCC阶段或在诊断之前血浆cfDNA，因此可用于HCC风险评估 和早期发现。在目标1中，我们将确定NASH相关HCC的肿瘤基因组图谱， 在南德克萨斯州的西班牙裔，并确定（如果有的话）HCC在这一人群中的独特功能。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HCC体细胞 在Aim 1中鉴定的突变，在患有NASH相关HCC的患者的血浆cfDNA中。在目标3中，我们 确定目标2中鉴定的基于突变的模型的效用，并应用于cfDNA，在HCC风险中 使用两个大型基于人口的西班牙裔队列对德克萨斯州南部的西班牙裔进行预测。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支持。它将 代表了在服务不足的地区进行的与NASH、糖尿病和肥胖相关的HCC的最大基因组研究。 特别是受这些慢性疾病影响的人群。项目的影响和转化目标是：1） 为德克萨斯州南部的西班牙裔人口提供服务，该人口的健康和医疗保健差异很大， 糖尿病、肥胖、NASH和HCC的发病率;以及2）开发新的测试以在该人群中识别受试者， 在肝癌的高风险，并建立有效的监测和预防策略，提高生存率。

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.