In carcinogenesis, global DNA hypomethylation has been associated with activation of oncogenes and genomic instability,29 whereas hypermethylation of CpG (cytosine guanine dinucleotide) islands located especially in gene regulatory sequences (e.g., of the Ras target RASSF1A, the adhesion

molecule CDH1, and the cell cycle regulator p16/CDKN2/INK4A) resulted in transcriptional silencing.26, 30 Methylation changes may occur early in the process of cancer development, and CpG island hypermethylation of regulatory regions of tumor-relevant genes is a frequent event accumulating in multistep hepatocarcinogenesis.31 Only a few studies have analyzed the global and promoter-specific levels of DNA methylation in hepatocarcinogenesis. Selleckchem FK866 First published data have revealed clear differences in DNA methylation between HCC and surrounding nontumorous tissue based on specific promoter hypermethylation and global hypomethylation.32 In this regard, genomic hypomethylation correlated with genomic instability in HCC, whereas methylation of CpG islands was associated with poor prognosis.33 In addition, DNA methylation status correlated with tumor recurrence after hepatectomy, cancer-free survival, and overall survival.34

Using class comparison analysis, HBV-, HCV-, and alcohol-specific promoter methylation patterns have been described, suggesting etiology-dependent methylation in early stages of hepatocarcinogenesis.32 Knowledge about these modifications Dabrafenib nmr in tumorigenesis is certainly

fragmentary, but epigenetic analyses may represent valuable tools for diagnosis and classification in the early stages of liver tumor development. Most transcriptomic studies in HCC have used cDNA or oligonucleotide high-density microarrays. Despite varying technical platforms, biological controls, and mathematical algorithms, these approaches have identified partly novel tumor-relevant genes and networks (e.g., PEG10, insulin-like growth factor-II [IGF-II], Claudin10, RhoC, AP-1, and cell cycle regulators).14, 35-37 Some studies have correlated expression profiling data in HCC with etiology,8 selleck vascular invasion,38 drug response,13 recurrence,12 and survival.36 Unsupervised clustering of transcriptomic data provided subtyping of HCC that was related to tumor-associated inflammation as well as tumor cell proliferation and apoptosis.35, 39 Furthermore, specific expression signatures derived from global gene expression analyses correlated well with the histological classification of premalignant lesions (low- and high-grade Dysplastic Nodules) and HCCs.40 Ye et al.41 also demonstrated that transcriptomic signatures significantly differed between HCCs with and without metastatic spread, whereas expression profiles of respective primary and metastatic tumors varied only by a few genes. Hierarchical clustering has revealed that HCCs can be divided into subgroups based on transcript profiles. Lee et al.