Abstract 5002: Comprehensive DNA methylation profiling of human hepatocellular carcinoma

Abstract

Abstract <Background and aim> Transcriptional inactivation of several tumor suppressor genes via epigenetic mechanism has been reported in many types of cancers, including hepatocellular carcinoma (HCC), and thus has been considered as critical events in multistage carcinogenesis. We conducted a comprehensive genome-wide analysis to elucidate distribution and characteristics of genes that subject to cancer-related DNA methylation in human HCC, especially on the context of development of methylation alteration in early stage of human hepatocarcinogenesis. <Materials and methods> With written informed consent, five well-differentiated HCC tissues and two corresponding matched non-cancerous liver tissues were obtained at the time of hepatectomy (2 tumors) or orthotopic living-donor liver transplantation (3 tumors and 2 non-tumors). After bisulfite modification, the converted DNA was subject to hybridization on Infinium Human Methylation BeadChip 450K (Illumina, Inc., San Diego, CA) that includes 485,764 cytosine positions of the human genome including gene promoters and repetitive DNA elements. The methylation level for each CpG dinucleotides was represented as a beta value according to the fluorescent intensity ratio. In order to identify alteration of methylation profile between well-differntiated HCC and non-tumor liver, difference of average beta values between tumor and non-tumor was calculated. <Results> Of 25,978 CpG loci that represent each gene, differences of average beta values of 24,805 loci (95.5%) were within 30%. These were considered as constitutively methylated or unmethylated. Tumor-specific demethylation was found at 589 loci representing 414 genes. Of these, 85.0% were located outside CpG islands, shore or shelf. Tumor-specific demethylation rarely occurred within CpG islands (3.4%). On the other hand, tumor-specific DNA methylation was found at 137 loci representing 108 genes. Of these, 65.7% were located within CpG islands. According to previously published information (Lee, TI. et. al. Cell 125:301-313, 2006), 39 genes (36%) out of these 108 genes with tumor-specific methylation have been reported to be occupied with polycomb group protein SUZ12 in embryonic stem cells. <Conclusion> Tumor-specific methylation occurring at CpG islands, especially of polycomb target genes, may contribute to hepatocarcinogenesis. This finding further suggests an importance of epigenetic mechanism on developing human HCC. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5002. doi:1538-7445.AM2012-5002