Anwar Sumadi Lukman, Krech Till, Hasemeier Britta, Schipper Elisa, Schweitzer Nora, Vogel Arndt, Kreipe Hans, Lehmann Ulrich
Institute of Pathology, Medizinische Hochschule Hannover, Carl-Neuberg-Str. 1, 30625 Hannover, Germany ; Present address: Department of Surgery, Faculty of Medicine Universitas Gadjah Mada, Yogyakarta, 55281 Indonesia.
Institute of Pathology, Medizinische Hochschule Hannover, Carl-Neuberg-Str. 1, 30625 Hannover, Germany.
Clin Epigenetics. 2015 Oct 15;7:110. doi: 10.1186/s13148-015-0145-6. eCollection 2015.
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.
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's exact test p = 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.
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.
印记基因座的异常DNA甲基化是导致包括癌症在内的多种发育和病理疾病的重要分子机制。然而，在全球癌症死亡的第三大主要原因——肝细胞癌（HCC）中，关于DNA甲基化变化导致的印记缺陷的了解相对有限。因此，我们对原发性HCC标本和癌旁肝组织进行了印记基因座的全面定量DNA甲基化分析，这些印记基因座在健康肝组织中显示约50%的甲基化。
我们发现HCC中许多印记基因座存在频繁且广泛的DNA甲基化异常。对印记基因座的DNA甲基化模式进行无监督聚类分析，发现了甲基化程度中度和重度缺失的HCC亚组。印记基因座的低甲基化与总体生存率差显著相关（对数秩检验，p = 0.02）。印记基因座的去甲基化伴随着LINE-1甲基化的缺失，LINE-1是常用的全基因组DNA甲基化水平标志物（p < 0.001）。此外，我们发现印记基因座的甲基化缺失与CTNNB1突变的存在相关（Fisher精确检验p = 0.03）。对公开可用的全基因组甲基化数据集的重新分析证实了我们的发现。对良性肝肿瘤（肝细胞腺瘤（HCA）和局灶性结节性增生（FNH））、相应的相邻肝组织和健康肝组织的分析表明，印记基因座的异常DNA甲基化是HCC特有的。
我们的分析表明，人类HCC中印记基因座存在频繁且广泛的DNA甲基化异常，并确定了一个总体生存率较短的低甲基化亚组患者。
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