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.

Project Narrative Hepatocellular carcinoma (HCC) is one of the fastest growing causes of cancer-related deaths among Americans, and it disproportionately affects African Americans. Differences in prevalence of established HCC risk factors do not fully explain the 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. Using a genome-wide association study approach, our research aims to identify and validate genetic factors that predispose to the development of HCC in African Americans and contribute to the racial disparities in HCC incidence.