Loss of DNA methylation at imprinted loci is a frequent event in hepatocellular carcinoma and identifies patients with shortened survival

Aim/Background

To find a prognostic biomarker using dysregulation of DNA methylation at imprinted loci in human hepatocellular carcinoma.

Methods

Quantitiative DNA methylation analysis at all imprinted loci in primary HCC samples, adjacent peri-tumoral tissues, hepatocellular adenoma, and healthy liver.

Results

We found frequent and extensive DNA methylation aberrations at many imprinted loci in HCC. Unsupervised cluster analysis of DNA methylation patterns at imprinted loci revealed subgroups of HCCs with moderate and severe loss of methylation. Hypomethylation at imprinted loci correlated significantly with poor overall survival (log rank test, p = 0.02). Demethylation at imprinted loci was accompanied by loss of methylation at LINE-1, a commonly used marker for global DNA methylation levels (p < 0.001). In addition, we found that loss of methylation at imprinted loci correlated with the presence of a CTNNB1 mutation (Fisher exact test p = 0.03). Re-analysis of publically available genome-wide methylation data sets confirmed our findings. The analysis in benign liver tumors (hepatocellular adenoma / HCA and focal nodular hyperplasia / FNH), the corresponding adjacent liver tissues, and healthy liver tissues showed that aberrant DNA methylation at imprinted loci is specific for the process of malignant transformation.

Conclusions

Our analyses demonstrate frequent and widespread DNA methylation aberrations at imprinted loci in human HCC identifying a hypomethylated subgroup of patients with shorter overall survival.

Clinical trial identification

not applicable

Disclosure

All authors have declared no conflicts of interest.