Altered DNA Methylation Landscapes of Polycomb-Repressed Loci Are Associated with Prostate Cancer Progression and ERG Oncogene Expression in Prostate Cancer
Altered DNA Methylation Landscapes of Polycomb-Repressed Loci Are Associated with Prostate Cancer Progression and ERG Oncogene Expression in Prostate Cancer
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DOI：
10.1158/1078-0432.ccr-12-3139
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发表时间：
2013-07-01
影响因子：
11.5
通讯作者：
Bapat, Bharati
中科院分区：
文献类型：
--
作者：
Kron, Ken;Trudel, Dominique;Bapat, Bharati
目的：为了根据前列腺癌格里森评分（GS）和ERG癌基因表达状态评估差异甲基化“景观”，并确定多梳组（PcG）靶基因参与的程度，我们试图根据格里森评分和ERG表达评估前列腺癌的全基因组DNA甲基化谱。实验设计：通过差异甲基化杂交将来自39个前列腺癌标本的基因组DNA与CpG岛微阵列杂交。我们比较了格里森评分和 ERG 表达状态之间的甲基化谱以及按 ERG 表达状态分层的格里森评分。此外，我们将我们的数据集的结果与公开可用的良性前列腺细胞组蛋白修饰数据集进行了比较。结果：我们发现了数百个与格里森评分和 ERG 增加相关的不同差异甲基化区域 (DMR)。此外，通过将样本分为 ERG 阳性和 ERG 阴性，与 Gleason 评分相关的 DMR 数量大大增加，其中 ERG 阳性/GS 相关 DMR 主要是高甲基化而不是低甲基化。最后，我们发现格里森评分相关或 ERG 高甲基化 DMR 与良性上皮细胞中具有 PcG 特征（H3K27me3、SUZ12）和缺乏活性基因表达特征（H3K4me3、RNA pol II）的不同区域之间存在显着重叠。结论：这项工作根据格里森评分定义了前列腺癌的甲基化景观，并表明启动遗传事件可能会影响前列腺癌表观基因组，随着前列腺癌的进展，这种情况会进一步受到干扰。此外，良性细胞中具有沉默染色质特征的 CpG 岛特别容易受到前列腺癌相关的高甲基化的影响。 (C)2013 AACR。
Purpose: To assess differentially methylated "landscapes" according to prostate cancer Gleason score (GS) and ERG oncogene expression status, and to determine the extent of polycomb group (PcG) target gene involvement, we sought to assess the genome-wide DNA methylation profile of prostate cancer according to Gleason score and ERG expression.Experimental Design: Genomic DNA from 39 prostate cancer specimens was hybridized to CpG island microarrays through differential methylation hybridization. We compared methylation profiles between Gleason score and ERG expression status as well as Gleason score stratified by ERG expression status. In addition, we comparedresults from our dataset to publicly available datasets of histone modifications in benign prostate cells. Results: We discovered hundreds of distinct differentially methylated regions (DMR) associated with increasing Gleason score and ERG. Furthermore, the number of DMRs associated with Gleason score was greatly expanded by stratifying samples into ERG-positive versus ERG-negative, with ERG-positive/GS-associated DMRs being primarily hypermethylated as opposed to hypomethylated. Finally, we found that there was a significant overlap between either Gleason score-related or ERG-hypermethylated DMRs and distinct regions in benign epithelial cells that have PcG signatures (H3K27me3, SUZ12) and lack active gene expression signatures (H3K4me3, RNA pol II).Conclusions: This work defines methylation landscapes of prostate cancer according to Gleason score, and suggests that initiating genetic events may influence the prostate cancer epigenome, which is further perturbed as prostate cancer progresses. Moreover, CpG islands with silent chromatin signatures in benign cells are particularly susceptible to prostate cancer-related hypermethylation. (C)2013 AACR.