Global Levels of Histone Modifications Predict Prostate Cancer Recurrence

被引:151
作者
Ellinger, Joerg [1 ]
Kahl, Philip [2 ]
von der Gathen, Johannes [1 ]
Rogenhofer, Sebastian [1 ]
Heukamp, Lukas C. [2 ]
Guetgemann, Ines [2 ]
Walter, Bernhard [3 ]
Hofstaedter, Ferdinand [4 ]
Buettner, Reinhard [2 ]
Mueller, Stefan C. [1 ]
Bastian, Patrick J. [5 ]
von Ruecker, Alexander [2 ]
机构
[1] Univ Klinikum Bonn, Klin & Poliklin Urol, D-53105 Bonn, Germany
[2] Univ Klinikum Bonn, Inst Pathol, D-53105 Bonn, Germany
[3] Univ Klinikum Erlangen, Urol Univ Klin, Erlangen, Germany
[4] Univ Regensburg, Inst Pathol, Regensburg, Germany
[5] Univ Klinikum Grosshadern, Urol Klin & Poliklin, Munich, Germany
关键词
histone; methylation; prognosis; prostate cancer; epigenetics; RADICAL PROSTATECTOMY; BREAST-CANCER; GENE LOCI; HYPERMETHYLATION; EXPRESSION; ADENOCARCINOMA; HYPOMETHYLATION; DEMETHYLASES; ACETYLATION; PROGNOSIS;
D O I
10.1002/pros.21038
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
PURPOSE. Epigenetic alterations such as DNA methylation and histone modifications play important roles in carcinogenesis. It was reported that global histone modification patterns are predictors of cancer recurrence in various tumor entities. Our study was performed to evaluate histone lysine (H(x)K(y)) and histone acetyl (H(x)Ac) modifications in prostate tissue. MATERIALS AND METHODS. A tissue microarray with 113 prostate cancer (PCA), 23 non-malignant prostate tissues was stained with antibodies against H3K4 mono-(H3K4mel), di-(H3K4me2), tri-(H3K4me3) methylation, H3K9mel, H3K9me2, H3K9me3, H3 and H4 panacetylation (H3Ac, H4Ac). We also analyzed H3K4 methylation in patients with advanced PCA (hormone-refractory PCA-HRPC, n = 34; hormone-dependent PCA, n = 30). Sections were scored according the staining intensity and the proportion of epithelial cells showing nuclear staining. RESULTS. H3K4mel, H3K9me2, H3K9me3, H3Ac, and H4Ac were significantly reduced in PCA compared to non-malignant prostate tissue. H3Ac and H3K9me2 levels allowed discrimination of PCA and non-malignant prostate tissue highly specifically (> 91%) and sensitively (> 78%) as determined via ROC analyses (AUC > 0.91). Histone lysine methylation and histone acetylation marks were correlated with clinical-pathological parameters (i.e., digital rectal examination, preoperative PSA, pT-stage, lymph node metastasis, Gleason score). In addition, H3K4mel was a significant predictor of PSA recurrence following radical prostatectomy. H3K4mel, H3K4me2, and H3K4me3 levels were significantly increased in HRPC. CONCLUSIONS. Global histone modification levels may help to identify patients with adverse prognosis, and represent a target for the future therapy of PCA. Prostate 70: 61-69, 2010. (c) 2009 Wiley-Liss, Inc.
引用
收藏
页码:61 / 69
页数:9
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