Abstract
Abstract The aim of this study is to reveal the significance of DNA methylation alterations in precancerous conditions associated with hepatitis virus infection. Genome-wide DNA methylation analysis using Infinium HumanMethylation450 BeadChip (Illumina) has been performed in 36 specimens of normal liver tissue obtained from patients without hepatocellular carcinomas (HCCs), 12 and 24 specimens of noncancerous liver tissues obtained from hepatitis B virus (HBV) infection-positive and hepatitis C virus (HCV) infection-positive patients with HCCs, respectively, and 24 samples of HCC themselves. On 21,106 CpG sites, alterations of DNA methylation levels were already evident in tissue specimens showing chronic hepatitis and liver cirrhosis, which are considered to be precancerous conditions, compared to normal liver tissues, and were inherited by HCC themselves. Unsupervised hierarchical clustering analysis based on DNA methylation levels at the 21,106CpG sites appropriately classified tissue specimens into normal, precancerous and cancerous clusters, indicating that DNA methylation alterations may participate continuously in hepatocarcinogenesis from the precancerous stage until cancers have become established. The incidence of DNA methylation alterations was higher at the precancerous stage of HCV-positive patients than that of HBV-positive patients. The incidence of DNA methylation alterations that actually occurred at the chronic hepatitis and liver cirrhosis stages but were restored in HCC themselves, which may be associated with inflammation or fibrosis, but may not participate in carcinogenesis itself, was at the almost equal levels regardless of probe annotations or hepatitis viruses. Many Infinium probes showing DNA methylation alterations participating continuously in multistage hepatocarcinogenesis were shared between HBV-positive and HCV-positive patients: only a small number of probes showed HBV-positive patient-specific DNA methylation alterations. On the other hand, DNA hypermethylation on regions around the transcription start sites was especially frequent during carcinogenesis in HCV-positive patients. We now intend to make the carcinogenetic risk estimation based on DNA methylation profiles at the precancerous stage clinically practical using liver biopsy specimens obtained prior to interferon therapy from patients who are followed up because of chronic liver diseases. Citation Format: Eri Arai, Ying Tian, Masahiro Gotoh, Yoriko Takahashi, Hidenori Ojima, Tomoo Kosuge, Yae Kanai. Genome-wide DNA methylation analysis in precancerous conditions associated with hepatitis B virus and hepatitis C virus infection. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1055. doi:10.1158/1538-7445.AM2015-1055
Published Version
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