Epigenetic approaches in liver cancer epidemiology: Global DNA methylation in hepatocellular carcinoma cases and controls

Background: The incidence of hepatocellular carcinoma (HCC) in the US has increased from 1.4 per 100,000 in the late 1970s to 2.4 per 100,000 in the early 1990s. It may be beneficial to examine HCC from both, a population-based and a molecular perspective. DNA hypomethylation is an early event in hepatocarcinogenesis and a feature of genomic DNA derived from solid tumor tissues. However, there are no case-control studies correlating global DNA hypomethylation with HCC. Objectives: To analyze global epigenetic patterns in a hepatocellular carcinoma case-control sample. Methods: Frozen liver tissue from HCC patients and controls were obtained from the Cooperative Human Tissue Network. DNA was extracted using standard methods. DNA methylation patterns were obtained using HPLC for fraction separation and Mass Spectrometry for quantification. A two-sample t test was performed using Welch's approximation for samples with unequal variances. Results: A global methylation index measuring methylated cytidine relative to global cytidine in the genome was significantly lower (p-value = 0.0002) for all cases, mean = 2.39 (95% CI, 1.99, 2.80), when compared to controls, mean = 3.54 (95% CI, 3.16, 3.93). Discussion: Global DNA hypomethylation patterns were useful in distinguishing HCC cases from controls. These results suggest that a continuous global methylation index is a useful epigenetic biomarker for cancer research. Epigenetic biomarkers may inform screening, early detection, and treatment strategies for HCC. Further population based research is warranted to look for correlations in epigenetic patterns in tissue and blood of HCC cases and appropriate controls, adjusting for known risk factors.