Genetic Epidemiology of Hepatocellular Carcinoma in African Americans

项目总结/摘要 在过去的三十年里，肝细胞癌（HCC）成为美国增长最快的癌症。 由于不到10%的患者可以治愈，5年生存率不到20%，因此应注意HCC 预防是最重要的。在美国，HCC的发病率存在很大的种族/民族差异， 非裔美国人的发病率比非西班牙裔白人高2倍。流行率的差异 确定的HCC风险因素并不能完全解释非裔美国人不成比例的高HCC负担， 临床干预和政策，以缩小这些种族差距已基本无效， 关于这种差距如何产生的根本问题仍然没有答案。我们假设宿主基因 这些因素可能预测非裔美国人的HCC风险，并可能导致HCC发病率的种族差异。 在欧洲和亚洲血统人群中进行的全基因组关联研究（GWAS）已经取得了成功 在揭示肝癌的常见遗传风险等位基因方面。然而，肝癌的种系遗传学因基础疾病而异 疾病病因学和遗传血统。到目前为止，还没有在非裔美国人中进行HCC GWAS。一 非洲裔美国人HCC遗传学研究的障碍是缺乏全面的遗传学、流行病学和 环境风险因素数据来自一个大的病例队列。我们建议在非裔美国人中进行HCC的GWAS 使用经过验证的全州（德克萨斯州）癌症患者接触研究方法。在病例对照研究中，我们将 研究非洲人全基因组常见遗传变异与HCC风险之间的关系 美国人（Aim 1）;这些数据将首次提供对非洲血统HCC生殖系遗传学的见解 人口我们将使用独立的GWAS数据来验证我们的顶级命中并进行跨种族比较 评估遗传发现在人群中的可转移性。宿主遗传因素可能 也赋予肝硬化患者对HCC风险的易感性，肝硬化是HCC的前兆。因此，在目标2中， 我们将通过两项平行的病例对照研究来确定肝硬化进展为HCC的遗传风险因素： 比较肝硬化患者与对照组，以及比较HCC病例与肝硬化患者。如果变体与 在HCC与对照组比较（目标1）中有HCC，但在肝硬化与对照组比较（目标2）中没有， 我们还可以在没有肝硬化的情况下确定与HCC相关的遗传风险因素， HCC病例的亚群。由于早期发现肝癌是至关重要的，我们的最后一个目标（目标3）将使用信息 遗传和非遗传风险因素，以获得临床适用的风险综合预测模型 分层这将是迄今为止在非裔美国人中进行的最大规模的HCC和肝硬化研究。我们全面 在非裔美国人HCC非匹配队列中评估HCC风险的新遗传标志物 将对HCC的预防和早期发现产生重大的转化意义。

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.