Genetic Epidemiology of Hepatocellular Carcinoma in African Americans

非裔美国人肝细胞癌的遗传流行病学

• 批准号: 10734530
• 负责人: Aaron Peter Thrift
• 金额: $ 36.6万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-26 至 2028-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10734530
• 关键词: Affect; African American; African American population; African ancestry; Alleles; American; Architecture; Asian ancestry; Attention; Biological Specimen Banks; Cancer Etiology; Cancer Patient; Case/Control Studies; Categories; Cessation of life; Cirrhosis; Clinical; Data; Development; Disease; Disparity; Early Diagnosis; Environmental Risk Factor; Epidemiology; Ethnic Origin; Etiology; European; Evaluation; Genetic; Genetic Markers; Genetic Predisposition to Disease; Genetic Risk; Genetic Variation; Genetic study; Genotype; Germ-Line Mutation; Goals; Incidence; Individual; Infrastructure; Intervention; Investigation; Knowledge; Machine Learning; Malignant Neoplasms; Modeling; Molecular; Not Hispanic or Latino; Nucleotides; Pathway interactions; Patients; Pattern; Phase; Policies; Population; Predisposition; Prevalence; Prevention; Primary carcinoma of the liver cells; Race; Relative Risks; Research; Research Personnel; Resources; Risk; Risk Factors; Role; Survival Rate; Texas; Underserved Population; Validation; Variant; alpha-Fetoproteins; blood-based biomarker; cancer site; clinical application; cohort; comparison group; cost efficient; design; ethnic difference; ethnic disparity; follow-up; genetic epidemiology; genetic information; genetic risk factor; genetic variant; genome wide association study; genome-wide; high risk; high risk population; insight; liver cancer model; next generation sequencing; non-genetic; novel; polygenic risk score; prospective; racial difference; racial disparity; risk prediction; risk prediction model; risk stratification; risk variant; screening

Project Summary/Abstract Over the past three decades, hepatocellular carcinoma (HCC) emerged as the fastest growing cancer in the U.S. With cure being possible in less than 10% of patients and 5 year survival rates less than 20%, attention to HCC prevention is paramount. Large racial/ethnic disparities exist in the incidence of HCC in the U.S. where the incidence rates are now 2-fold higher in African Americans than non-Hispanic whites. Differences in prevalence of established HCC risk factors do not fully explain the disproportionately high HCC burden in African Americans, and clinical interventions and policies to close these racial gaps have been largely ineffective because fundamental questions about how this disparity arises remain unanswered. We hypothesize that host genetic factors may predict HCC risk in African Americans and may contribute to the racial disparities in HCC incidence. Genome-wide association studies (GWAS) in European and Asian descent populations have been successful in revealing common genetic risk alleles for HCC. However, germline genetics of HCC varies by the underlying disease etiology and by genetic ancestry. To date, no HCC GWAS has been performed in African Americans. A barrier to genetic studies of HCC in African Americans is the lack of comprehensive genetic, epidemiological and environmental risk factor data from a large cohort of cases. We propose a GWAS of HCC in African Americans using a proven state-wide (Texas) cancer patient contact study approach. In a case-control study, we will investigate the relationship between common genetic variation genome-wide and the risk of HCC in African Americans (Aim 1); these data will provide first insights into the germline genetics of HCC in an African ancestry population. We will use independent GWAS data to validate our top hits and to perform cross-race comparisons to assess the transferability of genetic findings across populations. It is plausible that host genetic factors may also confer susceptibility to HCC risk among patients with cirrhosis, the precursor for HCC. Therefore, in Aim 2, we will identify genetic risk factors for cirrhosis progression to HCC using two parallel case-control studies: comparing cirrhosis patients with controls, and comparing HCC cases with cirrhosis patients. If variants associate with HCC in the HCC versus control comparison (Aim 1) but not the cirrhosis versus control comparison (Aim 2), we may also identify genetic risk factors associated with HCC in the absence of cirrhosis, a potentially growing sub-population of HCC cases. Because early detection of HCC is critical, our last aim (Aim 3) will use information on genetic and non-genetic risk factors to derive clinically applicable comprehensive prediction models for risk stratification. This will be the largest study to date of HCC and cirrhosis in African Americans. Our comprehensive evaluation of novel genetic markers underlying HCC risk in an unmatched cohort of African Americans with HCC will have major translational implications for HCC prevention and early detection.

项目摘要/摘要 在过去的三十年中，肝细胞癌（HCC）成为美国生长最快的癌症 在不到10％的患者和5年生存率的情况下可以治愈，注意力少于20％，注意HCC 预防至关重要。在美国，HCC发病率存在着巨大的种族/种族差异 现在，非裔美国人的发病率比非西班牙裔白人高2倍。患病率的差异 既定的HCC危险因素并不能完全解释非洲裔美国人的HCC负担不成比例的， 临床干预措施和缩小这些种族歧视的政策在很大程度上是无效的，因为 关于这种差异如何产生的基本问题仍未得到答复。我们假设宿主遗传 因素可能会预测非裔美国人的HCC风险，并可能导致HCC发病率的种族差异。 欧洲和亚洲血统中的全基因组协会研究（GWAS）已经成功 在揭示HCC的常见遗传风险等位基因时。但是，HCC的种系遗传学因基础而异 疾病病因和遗传血统。迄今为止，在非洲裔美国人中还没有进行HCC GWAS。一个 非洲裔美国人中HCC遗传研究的障碍是缺乏全面的遗传，流行病学和 来自大量病例的环境风险因素数据。我们在非裔美国人中提出了HCC的GWA 使用经过验证的全州（得克萨斯州）癌症患者接触研究方法。在一项案件对照研究中，我们将 研究非洲人的常见遗传变异基因组和HCC风险之间的关系 美国人（目标1）；这些数据将提供对非洲血统中HCC种系遗传学的首先见解 人口。我们将使用独立的GWAS数据来验证我们的最高点击并执行跨竞赛比较 评估遗传发现跨种群的转移性。宿主遗传因素可能是合理的 肝硬化患者（HCC的前体）也赋予对HCC风险的敏感性。因此，在AIM 2中， 我们将使用两项平行病例对照研究确定肝硬化进展为HCC的遗传危险因素： 将肝硬化患者与对照组进行比较，并将HCC病例与肝硬化患者进行比较。如果变体关联 在HCC与控制比较中进行HCC（AIM 1），但没有肝硬化与控制比较（AI​​M 2）， 我们还可以在没有肝硬化的情况下鉴定与HCC相关的遗传危险因素，这是一种潜在的增长 HCC病例的子人群。因为早期对HCC的发现至关重要，所以我们的最后一个目标（AIM 3）将使用信息 关于遗传和非遗传危险因素，以得出临床适用的风险综合预测模型 分层。这将是迄今为止在非洲裔美国人中进行HCC和肝硬化的最大研究。我们的全面 评估与HCC无与伦比的非裔美国人队列中HCC风险的新遗传标记 将对HCC预防和早期检测具有重大的翻译意义。