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CpG island hypermethylation and repetitive DNA hypomethylation in premalignant lesion of extrahepatic cholangiocarcinoma

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Abstract

Biliary intraepithelial neoplasia (BilIN) is the premalignant lesion of extrahepatic cholangiocarcinoma (EHC), and there are no published data regarding epigenetic changes throughout disease progression from normal biliary epithelia to BilIN to EHC. The objective of this study was to identify the occurrence of CpG island hypermethylation and repetitive DNA hypomethylation in BilIN. A total of 50 EHCs, 31 BilINs, and 31 normal cystic duct samples were analyzed for their methylation status in seven genes and two repetitive DNA elements. The number of methylated genes increased with disease progression (normal bile duct, 0.6; BilIN, 2.0; EHC, 3.6; P < 0.001). The methylation level of examined genes was significantly higher in BilIN than in normal samples (TMEFF2, HOXA1, NEUROG1, and RUNX3, P < 0.05) and in EHC than in BilIN samples (TMEFF2, HOXA1, NEUROG1, RUNX3, RASSF1A, and APC, P < 0.05). Long interspersed nucleotide element-1 (LINE-1) and juxtacentromeric satellite 2 (SAT2) methylation levels were markedly lower in EHC than in normal duct and BilIN samples, and BilIN samples showed a decrease of SAT2 methylation levels but no decrease of LINE-1 methylation levels compared to normal samples. These findings suggest that most of cancer-specific CpG island hypermethylation occur in the stage of BilIN and that CpG island hypermethylation seems to occur earlier than repetitive DNA element hypomethylation.

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Acknowledgments

This study was supported by a grant from the Cancer Research Institute Research Fund, a grant from the Seoul National University Hospital Research Fund (03-2008-020-0), and the Korea Research Foundation Grant (MOEHRD; KRF-2008-041-E00099).

Conflict of interest

The authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. Department of Pathology, Korea University Medical School, Seoul, South Korea

    Baek-hui Kim

  2. Laboratory of Epigenetics, Cancer Research Institute and BK21 2nd Stage, College of Medicine, Seoul National University, Seoul, South Korea

    Nam-Yun Cho, So Hyun Shin & Gyeong Hoon Kang

  3. Department of Pathology, College of Medicine, Seoul National University, 28 Yongon-dong, Jongno-gu, Seoul, 110-744, South Korea

    Hyeong-Ju Kwon, Ja June Jang & Gyeong Hoon Kang

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  1. Baek-hui Kim
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  2. Nam-Yun Cho
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Correspondence to Gyeong Hoon Kang.

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Supplement Table 1

Histologic features of EHCs and BilINs (DOC 124 kb)

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Kim, Bh., Cho, NY., Shin, S.H. et al. CpG island hypermethylation and repetitive DNA hypomethylation in premalignant lesion of extrahepatic cholangiocarcinoma. Virchows Arch 455, 343–351 (2009). https://doi.org/10.1007/s00428-009-0829-4

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  • DOI: https://doi.org/10.1007/s00428-009-0829-4

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