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Abstract
BackgroundSecreted 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.MethodsWIF1 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.ResultsWIF1 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.ConclusionAlthough 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.
Highlights
Secreted Wnt signaling antagonists have recently been described as frequent targets of epigenetic inactivation in human tumor entities
Wnt-inhibitory factor-1 (WIF1) promoter methylation in primary breast carcinomas WIF1 promoter methylation in human breast cancer has been previously reported by Ai et al [11], who demonstrated, by use of Methylation-specific polymerase chain reaction (PCR) (MSP), WIF1 methylation in 16 of 24 (67%) breast carcinoma samples
In their study the WIF1 promoter regions investigated by MSP and bisulfite genomic sequencing (BGS) were not matching or overlapping, so we decided to analyze WIF1 promoter methylation in breast cancer by MSP in the particular promoter region that has been covered by BGS in the other study (Figure 1A)
Summary
Secreted Wnt signaling antagonists have recently been described as frequent targets of epigenetic inactivation in human tumor entities. Promoter methylation effectively represses RNA transcription and occurs in many genes involved in human cancer development [2] The majority of these affected genes are potential or known tumor suppressor genes that are regulators of different cellular pathways, such as cell cycle, DNA repair, growth factor signaling or cell adhesion [3]. Several lines of evidence suggest that in breast cancer the Wnt signaling pathway is disrupted predominantly through epigenetic aberrations, most of all by promoter methylation of genes encoding secreted Wnt inhibitory molecules. Two studies reported frequent methylation of the APC gene in breast carcinomas [14,15] This provides strong evidence for an epigenetically disrupted and thereby activated Wnt signaling pathway in the development of human breast cancer
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