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

Jun Yu, Qian Tao, Yuen Y. Cheng, Kwan Y. Lee, Simon S.M. Ng, Kin F. Cheung, Linwei Tian, Sun Y. Rha, Ulf Neumann, Christoph Röcken, Matthias P.A. Ebert, Francis K.L. Chan, Joseph J.Y. Sung

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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.

Original languageEnglish
Pages (from-to)49-60
Number of pages12
JournalCancer
Volume115
Issue number1
DOIs
Publication statusPublished - 2009 Jan 1

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Catenins
Methylation
Stomach Neoplasms
Survival
Colorectal Neoplasms
Cell Line
Neoplasms
Wnt Signaling Pathway
Kaplan-Meier Estimate
Survival Analysis
Epigenomics
Colonic Neoplasms
Genes
Stomach
Multivariate Analysis
Confidence Intervals
Gene Expression
Growth

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

Cite this

Yu, J., Tao, Q., Cheng, Y. Y., Lee, K. Y., Ng, S. S. M., Cheung, K. F., ... Sung, J. J. Y. (2009). Promoter methylation of the Wnt/β-catenin signaling antagonist Dkk-3 is associated with poor survival in gastric cancer. Cancer, 115(1), 49-60. https://doi.org/10.1002/cncr.23989
Yu, Jun ; Tao, Qian ; Cheng, Yuen Y. ; Lee, Kwan Y. ; Ng, Simon S.M. ; Cheung, Kin F. ; Tian, Linwei ; Rha, Sun Y. ; Neumann, Ulf ; Röcken, Christoph ; Ebert, Matthias P.A. ; Chan, Francis K.L. ; Sung, Joseph J.Y. / Promoter methylation of the Wnt/β-catenin signaling antagonist Dkk-3 is associated with poor survival in gastric cancer. In: Cancer. 2009 ; Vol. 115, No. 1. pp. 49-60.
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title = "Promoter methylation of the Wnt/β-catenin signaling antagonist Dkk-3 is associated with poor survival in gastric cancer",
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.",
author = "Jun Yu and Qian Tao and Cheng, {Yuen Y.} and Lee, {Kwan Y.} and Ng, {Simon S.M.} and Cheung, {Kin F.} and Linwei Tian and Rha, {Sun Y.} and Ulf Neumann and Christoph R{\"o}cken and Ebert, {Matthias P.A.} and Chan, {Francis K.L.} and Sung, {Joseph J.Y.}",
year = "2009",
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Yu, J, Tao, Q, Cheng, YY, Lee, KY, Ng, SSM, Cheung, KF, Tian, L, Rha, SY, Neumann, U, Röcken, C, Ebert, MPA, Chan, FKL & Sung, JJY 2009, 'Promoter methylation of the Wnt/β-catenin signaling antagonist Dkk-3 is associated with poor survival in gastric cancer', Cancer, vol. 115, no. 1, pp. 49-60. https://doi.org/10.1002/cncr.23989

Promoter methylation of the Wnt/β-catenin signaling antagonist Dkk-3 is associated with poor survival in gastric cancer. / Yu, Jun; Tao, Qian; Cheng, Yuen Y.; Lee, Kwan Y.; Ng, Simon S.M.; Cheung, Kin F.; Tian, Linwei; Rha, Sun Y.; Neumann, Ulf; Röcken, Christoph; Ebert, Matthias P.A.; Chan, Francis K.L.; Sung, Joseph J.Y.

In: Cancer, Vol. 115, No. 1, 01.01.2009, p. 49-60.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Promoter methylation of the Wnt/β-catenin signaling antagonist Dkk-3 is associated with poor survival in gastric cancer

AU - Yu, Jun

AU - Tao, Qian

AU - Cheng, Yuen Y.

AU - Lee, Kwan Y.

AU - Ng, Simon S.M.

AU - Cheung, Kin F.

AU - Tian, Linwei

AU - Rha, Sun Y.

AU - Neumann, Ulf

AU - Röcken, Christoph

AU - Ebert, Matthias P.A.

AU - Chan, Francis K.L.

AU - Sung, Joseph J.Y.

PY - 2009/1/1

Y1 - 2009/1/1

N2 - 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.

AB - 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.

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