Genomicand environmental drivers of HCC in Non-Hispanic Blacks: Nature and nurture: Non-Hispanic Black Americans (Blacks) develop hepatocellular carcinoma (HCC) at about twice the rate of Whites and have far higher mortality. HCC has an atypical presentation in Blacks, with lower cirrhosis stage at the time of HCC diagnosis and more advanced and aggressive HCC. Blacks have higher exposure to environmental pollutants than Whites and these exposures are associated with liver damage. Although heavy metals and toxins are known to cause liver injury and cancer, they are often overlooked. This project addresses the need to understand the genomic and environmental factors causing the atypical presentation of HCC in Blacks so that effective prevention and treatment strategies can be implemented. It is responsive to RFA-CA- 23-023 in the topic area: Liver cancer in underserved minority populations. This innovative collaboration between experts in the Liver Cirrhosis Network and liver cancer researchers is expected to yield actionable mechanistic insights into environmental exposures, tumor immunophenotype, and genetic factors driving the atypical presentation of HCC in Blacks and may identify new targets for intervention and prevention. The study will also yield a polygenic risk score for cirrhosis for use among ancestrally diverse populations. The results will alert patients and providers to the fact that HCC risk is disproportionate to cirrhosis stage in Blacks, raising awareness of the threat and encouraging early enrollment in surveillance. This project will expand HCC tumor sequencing and transcriptomic data from Black patients over 4-fold. The Cancer Genome Atlas (TCGA) has only 17 HCCs from Blacks. Aim I: Hypothesis: Mutational signatures of toxic damage are more prevalent in HCCs of Blacks than in HCCs of Whites. We will perform whole exome sequencing on paired HCC/non-HCC specimens from Blacks and use our in-house pipeline to identify somatic single nucleotide variants (SNVs), to find known and novel mutational signatures, to define the tumor mutational burden, and to identify mutated genes. Aim II: Hypothesis: The HCC tumor cells and surrounding microenvironment in Blacks are primed for pro-tumor activity. We will perform global transcriptomic analysis on paired HCC/non-HCC specimens of Blacks to identify oncogenic drivers and computationally immunophenotype the microenvironment. Multiplexed IHC will be used to map the molecular findings onto the histological architecture of the patient's human liver specimens. Aim III: Hypothesis: Blacks with HCC have a lower prevalence of cirrhosis risk variants than Whites with HCC, but they have a high prevalence of cancer risk variants, including rare penetrant variants. We will compare the prevalence of cancer predisposition variants in Blacks with HCC vs. healthy controls, develop score cirrhosis a polygenic risk for cirrhosis, compare cirrhosis risk between Blacks and Whites with HCC, and explore genetic...