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Review
. 2011 Jun;13(6):369-76.
doi: 10.1111/j.1477-2574.2011.00303.x. Epub 2011 Mar 29.

Clinical implications of DNA methylation in hepatocellular carcinoma

Eric L Sceusi  1 , David S Loose, Curtis J Wray
Affiliations
Review

Clinical implications of DNA methylation in hepatocellular carcinoma

Eric L Sceusi et al. HPB (Oxford). 2011 Jun.

Abstract

Background: Epigenetics is a rapidly evolving field of genetic study applicable to nearly every aspect of genome-related research. The importance of epigenetics has been recognised in human hepatocellular carcinoma (HCC). Changes in DNA methylation patterns, including global hypomethylation and promoter hypermethylation, are thought to be early events in hepatocarcinogenesis.

Objectives: This review aimed to summarise the role of epigenetics in HCC, to describe the mechanisms of epigenetic changes in HCC and to examine the clinical relevance of epigenetics in HCC.

Methods: This review examines the role of CpG-rich regions and DNA methylation, and describes an epigenetic model of cancer, tumour type-specific methylation, the relationships among methylation, cirrhosis and hepatocarcinogenesis, and the role of DNA methylation in HCC. The clinical implications of epigenetics in HCC are discussed.

Results: A multivariate predictor model based on traditional clinical factors and DNA methylation profile may have important applications in the early detection of neoplastic transformation in populations at high risk for HCC. CpG methylation may be valuable in HCC prognostics. DNA methylation profiles may enable clinical prediction in pre-therapy patient biopsies, paraffin-embedded samples or plasma DNA.

Conclusions: Epigenetic changes and profiles may correlate to the biological behaviour of tumours and clinical outcome of HCC patients. The use of DNA methylation profiles as a surrogate biomarker remains an active area of clinical cancer research.

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Figures

Figure 1
Figure 1
Schematic demonstrating how epigenetic DNA methylation blocks gene promoter function. (A) Areas rich in cytosine-phosphate-guanine (CpG) are preferentially located at or near promoters of genes. Normal gene expression is promoted by zinc finger proteins (Zn fingers) and histone demethylases inhibiting methylation of the CpG sites. (B) Loss of Zn finger and histone demethylase proteins and/or increased 5-DNA methyltransferase activity results in increased CpG methylation and subsequent gene silencing. Silencing of tumour suppressor genes in this manner can lead to carcinogenesis
Figure 2
Figure 2
Progenitor cell model of DNA methylation and hepatocarcinogenesis. The development of cancer is initiated by a genetic or epigenetic ‘first hit’, which increases progenitor cell proliferation. A genetic and epigenetic ‘second hit’ results in neoplastic transformation of a progenitor cell or a ‘colour shift’ of a population of cells. These transformed cancer cells proliferate to form a tumour and, through increased genetic and epigenetic instability, develop additional phenotypes resulting in heterogeneous tumour cell populations
Figure 3
Figure 3
The role of cirrhosis as it relates to DNA methylation. Cirrhosis plays an important role in the development of hepatocellular carcinoma (HCC). This can result from epigenetic changes and can also cause epigenetic and genetic changes that ultimately lead to HCC. HCV, hepatitis C virus; HBV, hepatitis B virus
Figure 4
Figure 4
Proposed pathway relating epidemiological exposures to the development of hepatocellular carcinoma (HCC). Acquired disease results in chronic hepatic insults, which accumulate and result in the development of HCC. HCV, hepatitis C virus; HBV, hepatitis B virus
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