PROGRAM SUMMARY / ABSTRACT This application is being submitted in response to the Notice of Special Interest (NOSI) identified as NOT- CA-24-032. I currently serve as PI/PD for the currently active (year 2 of 5) P01 CA263025 (Prevention of Hepatocellular Carcinoma Related to Metabolic Syndrome). Hepatocellular carcinoma (HCC) is one of the fastest growing causes of cancer deaths among Americans. In the past decade, there has been an epidemic increase in metabolic (dysfunction) associated fatty liver disease (MAFLD)-related cirrhosis and HCC. MAFLD is estimated to affect 1 billion individuals globally and is projected to become the leading cause of HCC in the next 2 decades. In the U.S., Hispanics are currently most affected by both MAFLD and HCC. There is an urgent need to develop effective strategies to reduce HCC burden in the growing MAFLD population. The overall goal of the Program Project is to reduce the burden of HCC-related mortality through better understanding of contemporary risk factors (e.g., metabolic traits and biomarkers) and protective factors (e.g., chemoprevention, HCC surveillance) of HCC related to MAFLD. We have established one of the largest and most characterized multiethnic cohort of persons with MAFLD-related cirrhosis, the Texas HCC Consortium (THCCC) Cohort. This Administrative Supplement aims to increase the impact of our THCCC research by adding measurements of multilevel factors. The goal of Project 1 of the parent Program Project is to identify risk factors and biomarkers associated with HCC risk among cirrhosis patients, such that those at highest risk can be targeted for prevention and early detection. This Administrative Supplement will increase and expand the influence of Project 1 by using multilevel factors characterizing genetic ancestries and neighborhood socioeconomic disadvantage to address important gaps in our understanding of heterogeneity in HCC risk within Hispanic populations with cirrhosis. Our Specific Aims are to: (1) examine the associations between genetic ancestry and HCC risk using admixture mapping analysis among Hispanic cirrhosis patients with (cases) and without HCC (controls) in the THCCC cohort; and (2) examine how the joint associations of genetic ancestry and neighborhood socioeconomic disadvantage affects HCC risk within Hispanic cirrhosis patients. The central hypotheses of this Supplement are that greater proportion of European ancestry and Indigenous ancestry (representing genetic influences) are associated with an increased risk of developing HCC, and that HCC risk within Hispanics with cirrhosis will vary by level of neighborhood disadvantage (representing environmental influences). The work proposed is relevant to the parent grant and its original work scope, but will provide important findings that will drive subsequent investigations and preventive measures to address the heterogeneity in HCC risk within the Hispanic population in the U.S.