Integrated analysis of genetic and epigenetic alterations in liver cancer.

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Background: Stepwise accumulation of genetic and epigenetic changes is widely observed in various types of cancer. Chromosomal deletion, promoter hypermethylation, or both mechanisms have been reported as common causes of functional loss of tumor suppressor genes. Recently, advances in high-density oligonucleotide microarray allows us to analyze these changes in genome-wide manner. Here, we applied this technologies to uncover landscape of genomic and epigenomic alterations on human liver cancer.
 Methods: For genome-wide analysis of promoter hypermethylation, we performed MeDIP-chip analysis (methylated DNA immunoprecipitation on tiling microarray) for hepatocellular carcinoma (HCC) and its adjacent liver tissue. Candidates of cancer-specific hypermethylated genes were selected out using this epigenomic profiling. Chromosomal alterations were analyzed by oligonucleotide genotyping microarray. Genomic regions with LOH (loss of heterozygosity) or with UPP (uniparental polysomy) were defined as potential regions of allelic loss.
 Result: MeDIP-chip analysis revealed hundreds of de novo hypermethylated genes in HCC. Lots of PcG (polycomb group protein) -targeted genes were listed as aberrantly hypermethylated genes, supporting the hypothesis of PcG-mediated repression of cancer-related genes. Allelic dosage analysis revealed precise location of LOH/UPP including commonly reported LOH regions in HCC; 8p, 13q, 17p.
 Conclusion: Microarray-based comprehensive analysis was useful not only to allow us to show landscape of genetic and epigenetic alterations in liver cancer, but also to identify novel candidates of functionally inactivated genes by both mechanisms in hepatocellular carcinoma.