UG3CA265842

Southern Liver Health Cohort - Project Summary/Abstract

Primary liver cancer, the vast majority of which is hepatocellular carcinoma (HCC), is one of the few cancers with increasing incidence in the US. Incidence of HCC has tripled since 1980, which is particularly worrisome given that HCC confers a median survival of less than two years. The steepest increases in incidence are in southern rural states and among ethnic minorities.

While the prevalence of HCC had paralleled high rates of viral hepatitis in the last several decades, recent increases in the prevalence of nonalcoholic fatty liver disease (NAFLD) and its progression to nonalcoholic steatohepatitis (NASH) with fibrosis and cirrhosis have fueled HCC in recent years. Yet, these factors alone do not explain the substantial regional and ethnic variation in HCC progression.

One understudied but potentially potent HCC risk factor with increasing prevalence that disproportionately affects ethnic minorities is exposure to environmental contaminants. These contaminants degrade slowly and therefore persist in the environment, providing a stable exogenous source for human exposure. Toxic metal(oid)s such as cadmium and arsenic are classified as probable carcinogens, and emerging data from murine models suggest that exposure is associated with hepatic steatosis, cirrhosis, and liver cancer. Per- and poly-fluoroalkyl substances (PFAS) exposure in humans is associated with obesity and NASH. Further, emerging evidence indicates that these environmental exposures can induce epigenetic alterations that may promote adverse effects on the liver, but we lack longitudinal human data.

These data underscore the need for longitudinal human data to assess whether and how these contaminants impact HCC risk. To address these knowledge gaps, and in response to RFA-CA-20-049, we propose the Southern Liver Health Study, a longitudinal cohort study of two sub-cohorts comprising 16,000 males and females aged 40 years and older in two southeastern states, North Carolina and Georgia.

We will test the overarching hypothesis that cadmium alone or in a mixture with other toxic metals and PFAS increases the risk of progression from NAFLD to liver fibrosis and HCC. The cohort will be recruited from community clinics including federally qualified health centers and university health systems' primary care centers and hepatology programs at Duke, UNC Chapel Hill, and Emory.

Sub-cohort I will comprise 10,000 otherwise healthy adults who will be followed for 1-5 years, anticipating that approximately 800 fibrosis cases, including cirrhosis, will develop. Sub-cohort II will comprise 6,000 advanced fibrosis cases, anticipating approximately 750 HCC cases will develop. We will nest case-control studies within the cohorts, evaluate associations between environmental exposures and HCC incidence, and identify epigenetic marks responsive to contaminants that predict progression to HCC.

Impact: This will be the first large-scale effort to longitudinally determine the link between environmental contaminants, liver disease, and cancer in a residentially and ethnically diverse population. Additionally, we will create a data and specimen repository that will provide the research community with an invaluable resource to study HCC and other cancers.

North Carolina State University

NOT APPLICABLE

93.113 - Environmental Health

National Cancer Institute (NCI) [HHS - NIH]

National Institute of Environmental Health Sciences (NIEHS) [HHS - NIH]

Raleigh, North Carolina 27695 United States

Single Zip Code

New Cohorts for Environmental Exposures and Cancer Risk (CEECR; UG3/UH3 Clinical Trial Not Allowed) (RFA-CA-20-049)

Amendment Since initial award the total obligations have increased 95% from $1,138,389 to $2,219,249.