The Impact of Genetic Ancestry on Racial Disparities in Hepatocellular Carcinoma Risk and Mortality

项目总结 在美国和世界范围内，肝细胞癌是癌症相关死亡的主要原因。 在肝癌风险方面存在显著的种族差异。黑人、西班牙裔和亚裔都增加了患肝癌的风险 与非西班牙裔白人相比。此外，黑人在被诊断为肝癌后的存活率一直是最低的。很有可能， 基因变异和基因-环境相互作用改变了肝癌的风险，也可能导致种族 肝细胞癌存活率的差异。这项建议的目标是利用我们已建立的多样化的队列 慢性肝病、肝硬变和肝癌患者如何识别基因变异，包括基因 血统，在已知风险因素和社会决定因素的背景下，导致肝癌风险和死亡率的差异 关于健康的。这个职业发展奖将为帕特里夏·琼斯博士提供经验，她是一位熟练的肝病专家 在临床流行病学方面，有机会获得遗传流行病学、遗传分析、 纵向数据分析和预测建模。了解遗传血统如何驱动肝癌风险 结果是识别与祖先相关的特定基因和途径的第一步 与风险增加和/或生存不良有关。在目标1中，我们将定义基因之间的关系 血统与肝癌风险：对200名肝癌患者和400名慢性肝病患者进行基因分型 来自美国国立卫生研究院的400名健康对照组和肝硬变患者。我们将根据以下因素定义肝细胞癌风险的差异 常见突变基因的跨基因组(全球)和特定染色体位置的遗传祖先 在肝癌中，如TERT、ARID1A、RB、CTNNB1、TP53、PNPLA3和IDH1/2。我们还将探索新的基因 当他们从正在进行的基因研究中出现时，他们会成为靶子。我们将建立并验证一个肝癌风险预测模型 它包含了基因祖先。通过将遗传和临床数据与个人社会因素和社会 对于健康的决定因素，拟议的项目将提高我们准确预测肝癌风险的能力。通过 通过区分高危患者，我们的风险分层工具可以改变目前的肝细胞癌筛查 范例。在目标2中，我们将使用200名肝细胞癌患者的基因数据来制定生存预测。 该模型结合了遗传祖先、社会决定因素和临床数据。我们将验证最终的生存 模型在两个不同的肝癌患者队列中。从我们的综合生存分析中获得的知识 在目标2中，将提高我们对生存差异的遗传决定因素的理解，并可能导致更多 对预后的准确估计，这是以患者为中心的关键结果。所接受的正式和体验式培训 通过课程作业、实习和研讨会，琼斯博士将能够发展出一种祖先信息的肝癌风险 将构成未来R01应用的基础的预测模型。在强大的多学科的指导下 具有肿瘤生物学、肝胆恶性肿瘤、遗传流行病学和社会领域专业知识的指导团队 决定因素，琼斯博士将发展新的和互补的技能，使她成为一个独立的 开展以患者为中心的综合性研究的调查员，为社区、诊所和实验室架起了桥梁。

PROJECT SUMMARY Hepatocellular carcinoma (HCC) is a leading cause of cancer-related death in the United States and worldwide. There are significant racial disparities in HCC risk. Blacks, Hispanics and Asians all have increased risk of HCC compared to non-Hispanic Whites. Also, Blacks consistently have the lowest survival after HCC diagnosis. Likely, genetic variation and gene-environment interactions modify HCC risk and may also contribute to racial differences in HCC survival. The objective of this proposal is to leverage our established cohort of diverse patients with chronic liver disease, cirrhosis and HCC to identify how genetic variation, including genetic ancestry, drives disparities in HCC risk and mortality, in the context of known risk factors and social determinants of health. This career development award will provide Dr. Patricia Jones, a skilled hepatologist with experience in clinical epidemiology, with the opportunity to gain additional training in genetic epidemiology, genetic analysis, longitudinal data analysis and predictive modeling. Understanding how genetic ancestry drives HCC risk and outcomes is the first step towards identifying specific ancestry-associated genes and pathways that are linked to increased risk and/or poor survival. In Aim 1, we will define the relationship between genetic ancestry and HCC risk by genotyping 200 participants with HCC, 400 participants with chronic liver disease ± cirrhosis and 400 healthy controls from the NIH All of Us study. We will define how HCC risk differs based on genetic ancestry across the genome (global) and at specific chromosomal locations for commonly mutated genes in HCC, e.g. TERT, ARID1A, RB, CTNNB1, TP53, PNPLA3, and IDH1/2. We will also explore new genetic targets as they emerge from ongoing genetic studies. We will build and validate an HCC risk-prediction model that incorporates genetic ancestry. By integrating genetic and clinical data with individual social factors and social determinants of health, the proposed project will improve our ability to accurately predict HCC risk. By distinguishing patients at highest risk, our risk stratification tool could transform the current HCC screening paradigm. In Aim 2, we will use genotype data from 200 participants with HCC to develop a survival prediction model that incorporates genetic ancestry, social determinants and clinical data. We will validate the final survival model in two separate cohorts of HCC patients. The knowledge gained from our comprehensive survival analysis in Aim 2 will improve our understanding of the genetic determinants of survival disparities and could lead to more precise estimates of prognosis, a key patient-centered outcome. The formal and experiential training received through coursework, internships and workshops will enable Dr. Jones to develop an ancestry-informed HCC risk prediction model that will form the basis of a future R01 application. With guidance from a strong multidisciplinary mentoring team with expertise in tumor biology, hepatobiliary malignancies, genetic epidemiology and social determinants, Dr. Jones will develop new and complementary skills enabling her to become an independent investigator who conducts integrative patient-oriented research that bridges the community, clinic and laboratory.