Genetic and Epigenetic Drivers of HCC in the Setting of NAFLD
Career Enhancement Program Overview
This proposal in the Hepatobiliary SPORE's Career Enhancement Program is investigating the applications of host genetic differences (risk variants or mutations) and epigenetic alterations (such as chemical changes to DNA) for the early detection of hepatocellular cancer (HCC) in the setting of nonalcoholic fatty liver disease (NAFLD).
Several biological markers have been explored previously but none were found to be reliable, sensitive and specific. New findings suggest that host genetic differences and epigenetic alterations may be useful for early detection of hepatocellular cancer. Inherited genetic differences can be used to prioritize targeted screening of people at high risk, while changes in circulating DNA can be used to detect an asymptomatic tumor early and allow surgical removal.
HCC is an often-fatal cancer. Many people who are diagnosed in the United States don't have a history of viral hepatitis or alcohol abuse, but their cancer often has features of nonalcoholic fatty liver disease (NAFLD). Indeed, NAFLD-related HCC cases are expected to rise in the United States, and because hepatitis B and C are associated with both NAFLD and hepatocellular cancer, it's critical to assess NAFLD-related HCC in the absence of these viral infections (that is, nonviral and nonalcohol HCC) to optimally reduce confounding.
Genetic and epigenetic differences in the one-carbon metabolism pathway have been strongly implicated in susceptibility to hepatocellular cancer in the setting of NAFLD. In animals, loss-of-function (LOF) mutations in some one-carbon metabolism genes (such as BHMT) leads to NAFLD development and progression to hepatocellular adenomas or HCC in 64% of murine models with the LOF mutations. In humans, genetic variation in certain one-carbon metabolism genes (such as PNPLA3) have been associated with increased risk of NAFLD and increased risk of HCC in a few small studies of candidate genes. These initial observations underscore the need for a comprehensive approach to study the role of one-carbon genes in hepatocellular cancer development in patients with nonalcoholic fatty liver disease.
Functionally, the one-carbon metabolism pathway mediates DNA methylation through the transfer of methyl groups to the 5th carbon of cytosine in DNA to form 5-methylcytosine (5mC, that is, DNA methylation). However, 5mC is not stable; it is converted to 5-hydroxymethylcytosine (5hmC) by TET enzymes. 5hmC is now recognized as an epigenetic mark that is distinct from 5mC.
Our preliminary data, as well as data from others, suggest that 5mC and 5hmC play plausible roles in HCC development and could serve as markers for use independently or integratively with other tumor markers or patient characteristics for early detection of hepatocellular cancer.