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.

项目摘要肝细胞癌（HCC）是美国和全球与癌症有关的主要原因。 HCC风险中有大量的种族分布。黑人，西班牙裔和亚洲人都有增加HCC的风险与非西班牙裔白人相比。此外，黑人在HCC诊断后的生存期限始终是最低的。可能，通用变异和基因环境相互作用改变了HCC风险，也可能有助于种族 HCC生存的差异。该提议的目的是利用我们既定的潜水员队列患有慢性肝病，肝硬化和HCC的患者，以确定遗传变异（包括遗传）如何在已知风险因素和社会决定者的背景下，祖先，驱动HCC风险和死亡率的分布健康。该职业发展奖将为熟练的肝病学家Patricia Jones博士提供经验在临床流行病学中，有机会获得遗传流行病学的额外培训，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HCC风险结果是确定特定祖先相关的基因和途径的第一步与增加的风险和/或生存不良有关。在AIM 1中，我们将定义通用之间的关系祖先和HCC风险通过基因分型为HCC的200名参与者，400名患有慢性肝病的参与者± NIH所有人研究的肝硬化和400个健康对照。我们将定义HCC风险根据跨基因组（全球）和通常突变基因的特定染色体位置的遗传血统在HCC中，例如TERT，ARID1A，RB，CTNNB1，TP53，PNPLA3和IDH1/2。我们还将探索新的通用目标是从正在进行的遗传研究中出现的。我们将建立和验证HCC风险预测模型结合了遗传血统。通过将遗传和临床数据与个体社会因素和社会相结合健康的决定因素，拟议的项目将提高我们准确预测HCC风险的能力。经过区分风险最高的患者，我们的风险分层工具可以改变当前的HCC筛查范例。在AIM 2中，我们将使用来自200名HCC参与者的基因型数据来开发生存预测结合遗传血统，社会决定者和临床数据的模型。我们将验证最终的生存在两名单独的HCC患者中模型。从我们的全面生存分析中获得的知识在AIM 2中，将提高我们对生存差异遗传决定者的理解，并可能导致更多预后的精确估计，这是一个以患者为中心的关键结果。正式和经验丰富的培训接受了通过课程，实习和研讨会将使琼斯博士能够发展祖先信息的HCC风险预测模型将构成未来R01应用程序的基础。在强大的多学科的指导下指导团队具有肿瘤生物学，肝胆道恶性肿瘤，遗传流行病学和社会方面的专业知识决定因素，琼斯博士将发展新的和完整的技能，使她成为独立的进行了综合面向患者的研究的研究者，桥接社区，诊所和实验室。