Identification of new differentially methylated genes that have potential functional consequences in prostate cancer.
Identification of new differentially methylated genes that have potential functional consequences in prostate cancer.
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DOI：
10.1371/journal.pone.0048455
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Xu J
中科院分区：
文献类型：
--
作者：
Kim JW;Kim ST;Turner AR;Young T;Smith S;Liu W;Lindberg J;Egevad L;Gronberg H;Isaacs WB;Xu J
许多差异甲基化基因已被确定在前列腺癌（PCa），主要是使用候选基因为基础的测定。最近，几个全球DNA甲基化谱已被报道在PCa，然而，这些都有弱点，在观察全球DNA甲基化改变PCa的能力。我们假设在PCa中仍然存在未鉴定的异常DNA甲基化，这可以使用更高分辨率的检测方法来鉴定。我们在PCa（n = 19）和邻近正常组织（n = 4）中使用了新开发的Illumina HumanMethylation 450 BeadChip，并将这些与基因表达数据相结合，以鉴定可能在PCa发展和进展中具有功能性后果的新DNA甲基化。 我们还在一个独立的数据集中证实了我们的甲基化结果。在另外56例PCa样本和55例癌旁正常组织中验证了两个异常DNA甲基化基因。总共28，735个CpG位点显示DNA甲基化的显著差异（FDR校正的P<0.05），其定义为PCa和正常样品之间至少20%的平均甲基化差异。此外，总共有122个基因在其启动子区域具有一个以上的差异甲基化CpG位点，并且基因表达模式与DNA甲基化的变化方向相反（例如，随着甲基化的增加，表达减少，反之亦然）。通过硫酸氢盐测序证实了AOX 1和SPON 2两个基因的异常DNA甲基化，其中大多数相应的CpG位点在肿瘤样品和正常组织之间显示出显著差异。AOX 1基因启动子区在54例PCa中有92.6%的样本出现甲基化，而在53例正常组织中只有3例出现甲基化。本研究使用一种新的BeadChip结合PCa中的基因表达数据来鉴定位于基因内的新的差异甲基化CpG位点。这些新发现的差异甲基化基因有可能作为前列腺癌诊断的生物标志物。
Many differentially methylated genes have been identified in prostate cancer (PCa), primarily using candidate gene-based assays. Recently, several global DNA methylation profiles have been reported in PCa, however, each of these has weaknesses in terms of ability to observe global DNA methylation alterations in PCa. We hypothesize that there remains unidentified aberrant DNA methylation in PCa, which may be identified using higher resolution assay methods. We used the newly developed Illumina HumanMethylation450 BeadChip in PCa (n = 19) and adjacent normal tissues (n = 4) and combined these with gene expression data for identifying new DNA methylation that may have functional consequences in PCa development and progression. We also confirmed our methylation results in an independent data set. Two aberrant DNA methylation genes were validated among an additional 56 PCa samples and 55 adjacent normal tissues. A total 28,735 CpG sites showed significant differences in DNA methylation (FDR adjusted P<0.05), defined as a mean methylation difference of at least 20% between PCa and normal samples. Furthermore, a total of 122 genes had more than one differentially methylated CpG site in their promoter region and a gene expression pattern that was inverse to the direction of change in DNA methylation (e.g. decreased expression with increased methylation, and vice-versa). Aberrant DNA methylation of two genes, AOX1 and SPON2, were confirmed via bisulfate sequencing, with most of the respective CpG sites showing significant differences between tumor samples and normal tissues. The AOX1 promoter region showed hypermethylation in 92.6% of 54 tested PCa samples in contrast to only three out of 53 tested normal tissues. This study used a new BeadChip combined with gene expression data in PCa to identify novel differentially methylated CpG sites located within genes. The newly identified differentially methylated genes may be used as biomarkers for PCa diagnosis.
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