Loss of DNA methylation at imprinted loci is a frequent event in hepatocellular carcinoma and identifies patients with shortened survival. Issue 1 (December 2015)

• Record Type: Journal Article
• Authors: Anwar, Sumadi; Krech, Till; Hasemeier, Britta; Schipper, Elisa; Schweitzer, Nora; Vogel, Arndt; Kreipe, Hans; Lehmann, Ulrich
• Is Part Of: Clinical epigenetics. Volume 7:Issue 1(2015)
• Page Start: 1
• Page End: 10
• Publication Date: 2015-12
• Subjects: Hepatocellular carcinoma -- Imprinting -- DNA methylation -- Pyrosequencing; Epigenesis -- Periodicals; Genetic regulation -- Periodicals; Human cytogenetics -- Periodicals; Human molecular genetics -- Periodicals; Cancer -- Genetic aspects -- Periodicals; 611.01816
• DOI: 10.1186/s13148-015-0145-6
• Languages: English
• ISSNs: 1868-7075

Abstract

Abstract Background Aberrant DNA methylation at imprinted loci is an important molecular mechanism contributing to several developmental and pathological disorders including cancer. However, knowledge about imprinting defects due to DNA methylation changes is relatively limited in hepatocellular carcinoma (HCC), the third leading cause of cancer death worldwide. Therefore, comprehensive quantitative DNA methylation analysis at imprinted loci showing ~50 % methylation in healthy liver tissues was performed in primary HCC specimens and the peritumoural liver tissues. 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 atLINE-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 aCTNNB1 mutation (Fisher's exact testp = 0.03). Re-analysis of publically available genome-wide methylation data sets confirmed our findings. The analysis of benign liver tumours (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 HCC. Conclusions Our analyses demonstrate frequent and widespread DNA methylation aberrations at imprinted loci in human HCC and identified a hypomethylated subgroup of patients with shorter overall survival.