Epigenetic Etiology of Human Liver Disease and the Impact of Alcohol and Hepatitis Viral Infection on the Epigenome
The impact of chronic alcohol abuse (EtOH) and hepatitis viral infection on the epigenome are studied, along with how epigenetic changes influence liver disease progression, and how these changes can be used to identify patients most at risk for disease progression.
Hepatocellular carcinoma (HCC) is a leading cause of cancer-related deaths worldwide and is one of the few tumor types whose incidence is increasing in the United States. Unlike many cancers, the predisposing risk factors for HCC are known, with chronic alcoholism and hepatitis B and C viral infection accounting for the majority of cases. In addition, HCC has a long clinical course and a well-defined precancerous state, cirrhosis. Interestingly, however, alcohol abuse and hepatitis viral infection do not appear to be mutagenic, suggesting an epigenetic component.
Studies in the laboratory focus on DNA methylation in HCC initiation and progression, as well as how alcohol use and viral infection impact the epigenome and cancer progression. DNA methylation and expression patterns are interrogated across the entire genome of primary human liver disease samples. This data is related to patient clinical-pathological data available and to cell culture model systems using cultured primary human hepatocytes.
Current results indicate that DNA methylation changes are robust; some are common to all environmental exposures while others are unique to alcohol or viral infection. This suggests that these agents act in distinct ways to promote HCC via the epigenome.
Given the poor prognosis of HCC patients, driven in part by therapy resistance and late stage of diagnosis, long-term project goals include development of noninvasive tests for human liver disease using DNA methylation markers to permit early detection and treatment. In addition, it is anticipated that elucidating the role of DNA methylation in HCC will provide new therapeutic targets.