Hypomethylation of long interspersed nuclear element-1 promoter is associated with poor outcomes for curative resected hepatocellular carcinoma

Authors

  • Xu-dong Gao,

    1. Department of Hepatology, Center of Therapeutic Research for Liver Cancer, The 302nd Hospital, Beijing, China
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    • Both authors contributed equally to this work.
  • Jian-hui Qu,

    1. Department of Hepatology, Center of Therapeutic Research for Liver Cancer, The 302nd Hospital, Beijing, China
    2. Beijing Institute for Infectious Disease, Beijing, China
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    • Both authors contributed equally to this work.
  • Xiu-juan Chang,

    1. Department of Hepatology, Center of Therapeutic Research for Liver Cancer, The 302nd Hospital, Beijing, China
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  • Yin-ying Lu,

    1. Department of Hepatology, Center of Therapeutic Research for Liver Cancer, The 302nd Hospital, Beijing, China
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  • Wen-lin Bai,

    1. Department of Hepatology, Center of Therapeutic Research for Liver Cancer, The 302nd Hospital, Beijing, China
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  • Hong Wang,

    1. Department of Hepatology, Center of Therapeutic Research for Liver Cancer, The 302nd Hospital, Beijing, China
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  • Zhong-xian Xu,

    1. Department of Hepatology, Center of Therapeutic Research for Liver Cancer, The 302nd Hospital, Beijing, China
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  • Lin-jing An,

    1. Department of Hepatology, Center of Therapeutic Research for Liver Cancer, The 302nd Hospital, Beijing, China
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  • Chun-ping Wang,

    1. Department of Hepatology, Center of Therapeutic Research for Liver Cancer, The 302nd Hospital, Beijing, China
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  • Zhen Zeng,

    1. Department of Hepatology, Center of Therapeutic Research for Liver Cancer, The 302nd Hospital, Beijing, China
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  • Yong-ping Yang

    Corresponding author
    1. Department of Hepatology, Center of Therapeutic Research for Liver Cancer, The 302nd Hospital, Beijing, China
    2. Beijing Institute for Infectious Disease, Beijing, China
    • Correspondence

      Yong-ping Yang, Center of Therapeutic Research for Liver Cancer, the 302nd Hospital, 100 Xi Si Huan Middle Road, Beijing, P.R. China

      Tel: +86 10 6693 3429

      Fax: +86 10 6387 9193

      e-mail: yongpingyang@hotmail.com

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Abstract

Background

Epigenetic alterations are well documented in hepatocarcinogenesis. However, hypomethylation of long interspersed nuclear element 1(LINE-1) promoter and its relationship with clinicopathological features in hepatocellular carcinoma (HCC) remain unknown.

Methods

The bisulfite-specific PCR and DNA sequencing analysis was performed to assess the methylation status of LINE-1 promoter in a pilot cohort of 71 patients with HCC. Additionally, methylation levels of two hot CpG sites of LINE-1 promoter, site 7 and 18 were measured by real-time PCR and compared with clinicopathological parameters in a cohort of 172 HCC. All the patients included were in BCLC stage A or B.

Results

Most patients with HCC (87.3%) showed hypomethylation of LINE-1 promoter compared with HBV-related cirrhosis and normal controls (P < 0.001). The HCC patients with LINE-1 promoter hypomethylation had a median tumour-free survival (TFS) and overall survival (OS) post-resection of 22.0 (95% CI: 13.3–30.7) months and 35.0 (95% CI: 24.0–46.1) months, respectively, compared with 40 months and ~60 months for those with LINE-1 promoter hypermethylation (P < 0.05). Multivariate analyses showed that the hypomethylation level at CpG site 7 and 18 of LINE-1 promoter, along with tumour size and tumour differentiation, was independently associated with both TFS and OS for patients with HCC after resection.

Conclusion

Promoter hypomethylation of LINE-1, especially at the CpG site 7 and 18, was associated with a poor prognosis in HCC.

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