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

遗传血统对肝细胞癌风险和死亡率种族差异的影响

基本信息

批准号：
10371567
负责人：
Patricia Denise Jones
金额：
$ 23.71万
依托单位：
UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-15 至 2027-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10371567
关键词：
ARID1A gene Address Admixture Advanced Malignant Neoplasm Affect African Asian Asian population Award Behavioral Biological Black Populations Black race Breast CTNNB1 gene Cancer Etiology Case-Control Studies Cessation of life Characteristics Cirrhosis Clinical Data Colon Cultural Diversity DNA Sequence Alteration Data Data Analyses Data Set Diagnosis Disease Educational workshop Enrollment European Fibrosis Financial Hardship Florida Foundations Funding Future Genes Genetic Genetic Determinism Genetic Variation Genetic study Genome Genomics Genotype Goals Haplotypes Hepatobiliary Hispanic Hispanic Populations Individual Inflammation Internships K-Series Research Career Programs Knowledge Laboratories Lead Link Liver diseases Malignant Neoplasms Malignant neoplasm of liver Mentors Mentorship Minority Modeling Mutate Native American Ancestry Native Americans Not Hispanic or Latino Outcome Panic Participant Pathway interactions Patient-Focused Outcomes Patients Performance Persons Phenotype Physicians Population Population Heterogeneity Prevalence Primary Malignant Neoplasm of Liver Primary carcinoma of the liver cells Prognosis Prospective cohort Prostate Race Research Research Personnel Risk Risk Factors Scientist Survival Analysis TP53 gene The Cancer Genome Atlas Time Training Training Activity Tumor Biology United States United States National Institutes of Health Variant base biobank cancer genetics cancer risk cancer survival chromosomal location chronic liver disease clinical epidemiology clinical phenotype cohort community clinic disorder control ethnic minority experience gene environment interaction genetic analysis genetic epidemiology hazard health care disparity health disparity hepatobiliary cancer high risk improved innovation mortality multidisciplinary novel patient oriented patient oriented research personalized approach phenotypic data precision medicine predictive modeling prognostication racial difference racial disparity racial diversity racial minority risk prediction model risk stratification risk variant screening skills social determinants social factors social health determinants socioeconomic diversity survival disparity survival prediction tool treatment strategy

项目摘要

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.

项目概要肝细胞癌（HCC）是美国和全世界癌症相关死亡的主要原因。 HCC 风险存在显着的种族差异，黑人、西班牙裔和亚洲人患 HCC 的风险均较高。此外，与非西班牙裔白人相比，黑人在诊断出肝癌后的生存率可能始终最低。遗传变异和基因-环境相互作用会改变 HCC 风险，也可能导致种族该提案的目的是利用我们已建立的多元化群体。慢性肝病、肝硬化和肝癌患者如何识别遗传变异，包括遗传在已知的风险因素和社会决定因素的背景下，血统导致 HCC 风险和死亡率的差异该职业发展奖将为帕特里夏·琼斯博士提供，她是一位经验丰富的熟练肝病学家。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模型了解遗传血统如何驱动 HCC 风险。和结果是确定特定祖先相关基因和途径的第一步在目标 1 中，我们将定义遗传之间的关系。通过对 200 名患有 HCC 的参与者和 400 名患有慢性肝病的参与者进行基因分型来确定血统和 HCC 风险 ± 我们将根据 NIH All of Us 研究中的肝硬化和 400 名健康对照来定义 HCC 风险的差异。跨基因组（全局）和特定染色体位置的常见突变基因的遗传祖先在 HCC 中，例如 TERT、ARID1A、RB、CTNNB1、TP53、PNPLA3 和 IDH1/2。我们将建立并验证 HCC 风险预测模型。通过将遗传和临床数据与个人社会因素和社会结合起来。健康的决定因素，拟议的项目将提高我们准确预测 HCC 风险的能力。区分最高风险的患者，我们的风险分层工具可以改变当前的 HCC 筛查在目标 2 中，我们将使用 200 名 HCC 参与者的基因型数据来制定生存预测。我们将验证最终的生存率。从我们的生存分析中获得的知识，我们在两个综合的 HCC 患者队列中建立了模型。目标 2 中的研究将提高我们对生存差异的遗传决定因素的理解，并可能导致更多预后的精确估计，以患者为中心的关键结果接受的正式和体验式培训。通过课程作业、实习和研讨会，琼斯博士将能够了解祖先的 HCC 风险预测模型将在强大的多学科指导下构成未来 R01 应用的基础。具有肿瘤生物学、肝胆恶性肿瘤、遗传流行病学和社会学专业知识的指导团队琼斯博士将开发新的补充技能，使她能够成为独立的决定因素进行以患者为导向的综合研究的研究者，在社区、诊所和实验室之间架起桥梁。