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Background  Secreted Wnt signaling antagonists have recently been described as frequent targets of epigenetic inactivation in human tumor entities. Since gene silencing of certain Wnt antagonists was found to be correlated with adverse patient survival in cancer, we aimed at investigating a potential prognostic impact of the two Wnt antagonizing molecules  WIF1  and  DKK3  in breast cancer, which are frequently silenced by promoter methylation in this disease.    Methods   WIF1  and  DKK3  promoter methylation were assessed by methylation-specific PCR with bisulfite-converted DNA from 19 normal breast tissues and 150 primary breast carcinomas. Promoter methylation was interpreted in a qualitative, binary fashion. Statistical evaluations included two-sided Fisher's exact tests, univariate log-rank tests of Kaplan-Meier curves as well as multivariate Cox regression analyses.    Results   WIF1 and DKK3  promoter methylation were detected in 63.3% (95/150) and 61.3% (92/150) of breast carcinoma samples, respectively. In normal breast tissues,  WIF1  methylation was present in 0% (0/19) and  DKK3  methylation in 5.3% (1/19) of samples. In breast carcinomas,  WIF1  methylation was significantly associated with methylation of  DKK3  (p = 0.009). Methylation of either gene was not associated with clinicopathological parameters, except for  DKK3  methylation being associated with patient age (p = 0.007). In univariate analysis,  WIF1  methylation was not associated with clinical patient outcome. In contrast,  DKK3  methylation was a prognostic factor in patient overall survival (OS) and disease-free survival (DFS). Estimated OS rates after 10 years were 54% for patients with  DKK3 -methylated tumors, in contrast to patients without  DKK3  methylation in the tumor, who had a favorable 97% OS after 10 years (p < 0.001). Likewise, DFS at 10 years for patients harboring  DKK3  methylation in the tumor was 58%, compared with 78% for patients with unmethylated  DKK3  (p = 0.037). Multivariate analyses revealed that  DKK3  methylation was an independent prognostic factor predicting poor OS (hazard ratio (HR): 14.4; 95% confidence interval (CI): 1.9–111.6; p = 0.011), and short DFS (HR: 2.5; 95% CI: 1.0–6.0; p = 0.047) in breast cancer.    Conclusion  Although the Wnt antagonist genes  WIF1  and  DKK3  show a very similar frequency of promoter methylation in human breast cancer, only  DKK3  methylation proves as a novel prognostic marker potentially useful in the clinical management of this disease.

Prognostic relevance of Wnt-inhibitory factor-1 (WIF1) and Dickkopf-3 (DKK3) promoter methylation in human breast cancer