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.

PROJECT NARRATIVE Hepatocellular carcinoma (HCC), also known as primary liver cancer, disproportionately affects minorities and the burden of this deadly disease has increased significantly. The proposed study will determine if genetic differences in African, European or Native American ancestry are responsible for the significant racial differences in liver cancer risk and survival, either directly or indirectly by interacting with other risk factors or social factors. Understanding which genetic features increase liver cancer risk or worsen survival could potentially improve our ability to (1) identify those people who are at highest risk and (2) develop screening and treatment strategies that are based on a person’s individualized risk.