Concurrent Hypermethylation of and Activates the Wnt/β-Catenin Pathway and Is Associated with Poor Prognosis in Patients with Gastric Cancer.

Aberrant hypermethylation of Wnt antagonists has been observed in gastric cancer. A number of studies have focused on the hypermethylation of a single Wnt antagonist and its role in regulating the activation of signaling. However, how the Wnt antagonists interacted to regulate the signaling pathway has not been reported. In the present study, we systematically investigated the methylation of some Wnt antagonist genes (, , , , , and ) and their regulatory role in carcinogenesis. We found that aberrant promoter methylation of , , , and was significantly increased in gastric cancer. Moreover, concurrent hypermethylation of and was observed in gastric cancer and this was significantly associated with increased expression of β-catenin, indicating that the joint inactivation of these two genes promoted the activation of the Wnt signaling pathway. Further analysis using a multivariate Cox proportional hazards model showed that methylation was an independent prognostic factor for poor overall survival, and the predictive value was markedly enhanced when the combined methylation status of and was considered. In addition, the methylation level of and was correlated with the patient's age and tumor differentiation, respectively. In conclusion, epigenetic silencing of Wnt antagonists was associated with gastric carcinogenesis, and concurrent hypermethylation of and could be a potential marker for a prognosis of poor overall survival.