Prognostic relevance of Wnt-inhibitory factor-1 WIF1 and Dickkopf-3 DKK3 promoter methylation in human breast cancerReportar como inadecuado

Prognostic relevance of Wnt-inhibitory factor-1 WIF1 and Dickkopf-3 DKK3 promoter methylation in human breast cancer - Descarga este documento en PDF. Documentación en PDF para descargar gratis. Disponible también para leer online.

BMC Cancer

, 9:217

First Online: 01 July 2009Received: 08 October 2008Accepted: 01 July 2009DOI: 10.1186-1471-2407-9-217

Cite this article as: Veeck, J., Wild, P.J., Fuchs, T. et al. BMC Cancer 2009 9: 217. doi:10.1186-1471-2407-9-217


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.

AbbreviationsBGSbisulfite genomic sequencing

BMBFBundesministerium für Bildung und Forschung

CIconfidence interval

DFSdisease-free survival


ERestrogen receptor

HRhazard ratio

MSPmethylation-specific polymerase chain reaction

NTCno template control

OSoverall survival

PCPplanar cell polarity pathway

PCRpolymerase chain reaction

PRprogesterone receptor

TCFT-cell factor

UICCInternational Union Against Cancer

UMDuniversal methylated DNA

UUDuniversal unmethylated DNA

WHOWorld Health Organization

WIF1Wnt-inhibitory factor 1.

Electronic supplementary materialThe online version of this article doi:10.1186-1471-2407-9-217 contains supplementary material, which is available to authorized users.

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Autor: Jürgen Veeck - Peter J Wild - Thomas Fuchs - Peter J Schüffler - Arndt Hartmann - Ruth Knüchel - Edgar Dahl


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