Prognostic relevance of Wnt-inhibitory factor-1 (WIF1) and Dickkopf-3 (DKK3) promoter methylation in human breast cancer.
Prognostic relevance of Wnt-inhibitory factor-1 (WIF1) and Dickkopf-3 (DKK3) promoter methylation in human breast cancer.
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DOI：
10.1186/1471-2407-9-217
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发表时间：
2009-07-01
期刊：
影响因子：
3.8
通讯作者：
Dahl E
中科院分区：
文献类型：
--
作者：
Veeck J;Wild PJ;Fuchs T;Schüffler PJ;Hartmann A;Knüchel R;Dahl E
最近，分泌型 Wnt 信号拮抗剂被描述为人类肿瘤实体表观遗传失活的常见靶标。由于某些 Wnt 拮抗剂的基因沉默被发现与癌症患者的不良生存相关，因此我们旨在研究乳腺癌中两种 Wnt 拮抗分子 WIF1 和 DKK3 的潜在预后影响，在这种疾病中，这两种分子经常被启动子甲基化沉默。使用来自 19 个正常乳腺组织和 150 个原发性乳腺癌的亚硫酸氢盐转化的 DNA，通过甲基化特异性 PCR 评估 WIF1 和 DKK3 启动子甲基化。以定性、二元方式解释启动子甲基化。统计评估包括两侧 Fisher 精确检验、Kaplan-Meier 曲线的单变量对数秩检验以及多元 Cox 回归分析。分别在 63.3% (95/150) 和 61.3% (92/150) 的乳腺癌样本中检测到 WIF1 和 DKK3 启动子甲基化。在正常乳腺组织中，WIF1 甲基化存在于 0% (0/19) 的样本中，DKK3 甲基化存在于 5.3% (1/19) 的样本中。在乳腺癌中，WIF1 甲基化与 DKK3 甲基化显着相关 (p = 0.009)。除了 DKK3 甲基化与患者年龄相关外，任一基因的甲基化均与临床病理参数无关 (p = 0.007)。在单变量分析中，WIF1 甲基化与临床患者结果无关。相比之下，DKK3 甲基化是患者总生存期 (OS) 和无病生存期 (DFS) 的预后因素。 DKK3 甲基化肿瘤患者的 10 年后估计 OS 率为 54%，而肿瘤中没有 DKK3 甲基化的患者 10 年后的 OS 率为 97%（p < 0.001）。同样，肿瘤中含有 DKK3 甲基化的患者 10 年时的 DFS 为 58%，而 DKK3 未甲基化的患者为 78%（p = 0.037）。多变量分析显示，DKK3 甲基化是乳腺癌中 OS 较差（风险比 (HR)：14.4；95% 置信区间 (CI)：1.9–111.6；p = 0.011）和 DFS 较短（HR：2.5；95% CI：1.0–6.0；p = 0.047）的独立预后因素。尽管 Wnt 拮抗剂基因 WIF1 和 DKK3 在人类乳腺癌中显示出非常相似的启动子甲基化频率，但只有 DKK3 甲基化被证明是一种新的预后标志物，在该疾病的临床管理中可能有用。
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. 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. 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. 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.
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影响因子：
6.4
作者：
Lecomte, T;Berger, A;Laurent-Puig, P
通讯作者：
Laurent-Puig, P
影响因子：
168.9
作者：
Müller, HM;Oberwalder, M;Widschwendter, M
通讯作者：
Widschwendter, M
DOI：
10.1073/pnas.93.18.9821
发表时间：
1996-09-03
影响因子：
11.1
作者：
Herman, JG;Graff, JR;Baylin, SB
通讯作者：
Baylin, SB
影响因子：
2.8
作者：
Oberwalder, Michael;Zitt, Marion;Mueller, Hannes M.
通讯作者：
Mueller, Hannes M.
影响因子：
4.7
作者：
Ai, Lingbao;Tao, Qian;Robertson, Keith D.
通讯作者：
Robertson, Keith D.