Promoter methylation of the Wnt/β-catenin signaling antagonist Dkk-3 is associated with poor survival in gastric cancer

Authors

  • Jun Yu MD, PhD,

    Corresponding author
    1. Institute of Digestive Disease and Department of Medicine, Chinese University of Hong Kong, Hong Kong SAR
    2. Li Ka Shing Institute of Health Sciences, State Key Laboratory in Oncology in South China, Chinese University of Hong Kong, Hong Kong SAR
    • Institute of Digestive Disease, Department of Medicine and Therapeutics, Chinese University of Hong Kong, Room 707A, Li Ka Shing Medical Sciences Building, Prince of Wales Hospital, Shatin, NT, Hong Kong SAR===

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    • Fax: (011) 852-21445330

  • Qian Tao PhD,

    1. Li Ka Shing Institute of Health Sciences, State Key Laboratory in Oncology in South China, Chinese University of Hong Kong, Hong Kong SAR
    2. Cancer Epigenetics Laboratory, Department of Clinical Oncology, Chinese University of Hong Kong, Hong Kong SAR
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  • Yuen Y. Cheng PhD,

    1. Institute of Digestive Disease and Department of Medicine, Chinese University of Hong Kong, Hong Kong SAR
    2. Li Ka Shing Institute of Health Sciences, State Key Laboratory in Oncology in South China, Chinese University of Hong Kong, Hong Kong SAR
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  • Kwan Y. Lee MS,

    1. Li Ka Shing Institute of Health Sciences, State Key Laboratory in Oncology in South China, Chinese University of Hong Kong, Hong Kong SAR
    2. Cancer Epigenetics Laboratory, Department of Clinical Oncology, Chinese University of Hong Kong, Hong Kong SAR
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  • Simon S. M. Ng MD,

    1. Department of Surgery, Chinese University of Hong Kong, Hong Kong SAR
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  • Kin F. Cheung MS,

    1. Institute of Digestive Disease and Department of Medicine, Chinese University of Hong Kong, Hong Kong SAR
    2. Li Ka Shing Institute of Health Sciences, State Key Laboratory in Oncology in South China, Chinese University of Hong Kong, Hong Kong SAR
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  • Linwei Tian MD, PhD,

    1. Stanley Ho Center for Emerging Infectious Disease, Chinese University of Hong Kong, Hong Kong SAR
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  • Sun Y. Rha PhD,

    1. Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, Korea
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  • Ulf Neumann MD, PhD,

    1. Department of General, Visceral, and Transplantation Surgery, Charite Campus Virchow-Klinikum, Charite University Hospital, Berlin, Germany
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  • Christoph Röcken MD, PhD,

    1. Institute of Pathology, Charite University Hospital, Berlin, Germany
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  • Matthias P. A. Ebert MD, PhD,

    1. Department of Medicine II, Technical University of Munich, Munich, Germany
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  • Francis K. L. Chan MD,

    1. Institute of Digestive Disease and Department of Medicine, Chinese University of Hong Kong, Hong Kong SAR
    2. Li Ka Shing Institute of Health Sciences, State Key Laboratory in Oncology in South China, Chinese University of Hong Kong, Hong Kong SAR
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  • Joseph J. Y. Sung MD, PhD

    1. Institute of Digestive Disease and Department of Medicine, Chinese University of Hong Kong, Hong Kong SAR
    2. Li Ka Shing Institute of Health Sciences, State Key Laboratory in Oncology in South China, Chinese University of Hong Kong, Hong Kong SAR
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Abstract

BACKGROUND:

Abnormal activation of the Wnt/β-catenin signaling pathway is common and critical in the pathogenesis of digestive cancers. In this study, the authors investigated the promoter methylation of the dickkopf homolog 3 gene Dkk-3 in these cancers and its prognostic significance in gastric cancer.

METHODS:

Dkk-3 methylation was assessed in 173 patients with gastric cancers (including 104 patients who were followed for up to 4090 days) and in 128 patients with colorectal cancer. Cell growth was evaluated by using a colony-formation assay. For survival analyses, the authors used Kaplan-Meier plots, the log-rank test, and Cox proportional regression.

RESULTS:

Dkk-3 was silenced or down-regulated in 12 of 17 gastric cancer cell lines (70.6%) and in 3 of 9 colon cancer cell lines (33.3%). The loss of gene expression was associated with promoter methylation, which could be restored by demethylating agents. Ectopic expression of Dkk-3 suppressed colony formation. Moreover, methylation of Dkk-3 was detected in 117 of 173 primary gastric tumors (67.6%) and in 67 of 128 colorectal tumors (52.3%). The clinical significance and the prognostic value of Dkk-3 methylation also were examined in 104 gastric cancers and in 84 colorectal cancers. Multivariate analysis indicated that Dkk-3 methylation was associated significantly and independently with poor disease survival (relative risk, 2.534; 95% confidence interval, 1.54–4.17; P = .002) in gastric cancer, but not in colorectal cancer. Kaplan-Meier survival curves revealed that patients who had Dkk-3 methylated gastric cancers had a significantly shorter survival (median, 0.76 years) compared with patients who did not have Dkk-3 methylation (median, 2.68 years; P < .0001; log-rank test).

CONCLUSIONS:

Epigenetic silencing of the Dkk-3 gene by promoter methylation was a common event in gastric cancer and was associated with a poor outcome in such patients. Cancer 2009. © 2008 American Cancer Society.

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