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首页> 外文期刊>BMC Medical Genomics >DNA methylation changes in ovarian cancer are cumulative with disease progression and identify tumor stage
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DNA methylation changes in ovarian cancer are cumulative with disease progression and identify tumor stage

机译：卵巢癌中的DNA甲基化变化随疾病进展而累积并确定肿瘤阶段

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Background Hypermethylation of promoter CpG islands with associated loss of gene expression, and hypomethylation of CpG-rich repetitive elements that may destabilize the genome are common events in most, if not all, epithelial cancers. Methods The methylation of 6,502 CpG-rich sequences spanning the genome was analyzed in 137 ovarian samples (ten normal, 23 low malignant potential, 18 stage I, 16 stage II, 54 stage III, and 16 stage IV) ranging from normal tissue through to stage IV cancer using a sequence-validated human CpG island microarray. The microarray contained 5' promoter-associated CpG islands as well as CpG-rich satellite and Alu repetitive elements. Results Results showed a progressive de-evolution of normal CpG methylation patterns with disease progression; 659 CpG islands showed significant loss or gain of methylation. Satellite and Alu sequences were primarily associated with loss of methylation, while promoter CpG islands composed the majority of sequences with gains in methylation. Since the majority of ovarian tumors are late stage when diagnosed, we tested whether DNA methylation profiles could differentiate between normal and low malignant potential (LMP) compared to stage III ovarian samples. We developed a class predictor consisting of three CpG-rich sequences that was 100% sensitive and 89% specific when used to predict an independent set of normal and LMP samples versus stage III samples. Bisulfite sequencing confirmed the NKX-2-3 promoter CpG island was hypermethylated with disease progression. In addition, 5-aza-2'-deoxycytidine treatment of the ES2 and OVCAR ovarian cancer cell lines re-expressed NKX-2-3. Finally, we merged our CpG methylation results with previously published ovarian expression microarray data and identified correlated expression changes. Conclusion Our results show that changes in CpG methylation are cumulative with ovarian cancer progression in a sequence-type dependent manner, and that CpG island microarrays can rapidly discover novel genes affected by CpG methylation in clinical samples of ovarian cancer.
机译：背景启动子CpG岛的超甲基化以及相关的基因表达损失，以及可能破坏基因组稳定性的富含CpG的重复元件的低甲基化在大多数（如果不是全部）上皮癌中都是常见的事件。方法分析了从正常组织到正常组织的137个卵巢样本（十个正常，23个低恶性潜能，18个I期，16个II期，54个III期和16个IV期）的卵巢基因样本中6,502个富含CpG的序列的甲基化。使用经序列验证的人CpG岛微阵列进行IV期癌症。该微阵列包含5'启动子相关的CpG岛，以及富含CpG的卫星和Alu重复元件。结果结果显示正常CpG甲基化模式随着疾病的进展而逐渐消退。 659个CpG岛显示出明显的甲基化损失或增加。卫星和Alu序列主要与甲基化的丧失有关，而启动子CpG岛构成了甲基化增加的大部分序列。由于大多数卵巢肿瘤在诊断时都处于晚期，因此我们测试了DNA甲基化谱图与III期卵巢样品相比是否可以区分正常和低恶性潜能（LMP）。我们开发了由三个富含CpG的序列组成的类预测器，当用于预测一组独立的正常和LMP样品（相对于III期样品）时，它们具有100％的敏感性和89％的特异性。亚硫酸氢盐测序证实NKX-2-3启动子CpG岛被甲基化与疾病进展。另外，对ES2和OVCAR卵巢癌细胞系的5-氮杂-2'-脱氧胞苷处理再次表达了NKX-2-3。最后，我们将CpG甲基化结果与先前发表的卵巢表达微阵列数据合并，并确定了相关的表达变化。结论我们的结果表明，CpG甲基化的改变随着卵巢癌进展而以序列类型依赖性方式累积，并且CpG岛微阵列可以在卵巢癌临床样品中快速发现受CpG甲基化影响的新基因。

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