Genomic and environmental drivers of HCC in Non-Hispanic Blacks: Nature and nurture

Hepatocellular carcinoma (HCC) is a major cause of cancer-related death and a leading cause of liver-related death. People are more likely to develop HCC if they have a chronic liver disease and chronic liver injury. Germline variants modulate the extent of scarring that occurs in response to chronic injury. Germline variants also influence the probability that HCC will arise. Germline variants interact with other factors (age, viral infections, toxic exposures, adiposity) to determine the risk that HCC will develop and to establish the characteristics of the tumor cells and their surrounding microenvironment. Specifically, the combination of genetic variants and other factors influence the types of somatic, cancer-associated DNA mutations and transcriptional changes that occur in HCC tumors. These tumors are highly heterogeneous in natural history and in their responses to cancer therapies. Because of this heterogeneity, it is critical to collect detailed information on all major HCC subclasses and to clarify the relationships among germline variants, disease presentation, and somatic cancer-related mutations. These factors influence therapeutic responses. Although five-year survival among patients with HCC is currently only about 20%, targeted therapies, including immune checkpoint inhibitors, are rapidly improving outcomes. Effective use of these therapies and the development of the next generation of precision medicines will require additional detailed information about HCC subclasses. To provide this information, this project is an innovative collaboration between experts in the Liver Cirrhosis Network and liver cancer researchers. It will yield information about the mutational signatures of HCCs in patients treated in the United States and investigate germline variants associated with advanced liver scarring (cirrhosis) and HCC. The results are expected to show that some types of cancer mutational profiles occur more frequently in individuals that have a low germline risk for cirrhosis. This information will help to identify patients who may benefit from initiating HCC screening at an earlier stage of liver cirrhosis than other patients. Aim I: We will perform whole exome sequencing on paired HCC/non-HCC specimens from HCC patients 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: We will perform global transcriptomic analysis on paired HCC/non-HCC specimens to identify oncogenic drivers and computationally immunophenotype the microenvironment. Multiplexed immunohistochemistry will be used to map the molecular findings onto the histological architecture of liver specimens. Aim III: We will compare the prevalence of cancer predisposition variants in people who do and who do not develop HCC, develop a polygenic risk score for cirrhosis, and explore genetic risks for cirrhosis in the Liver Cirrhosis Network.