Quantitative analysis of associations between DNA hypermethylation, hypomethylation, and DNMT RNA levels in ovarian tumors
Quantitative analysis of associations between DNA hypermethylation, hypomethylation, and DNMT RNA levels in ovarian tumors
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DOI：
10.1038/sj.onc.1209145
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发表时间：
2006-04-01
期刊：
影响因子：
8
通讯作者：
Laird, PW
中科院分区：
文献类型：
--
作者：
Ehrlich, M;Woods, CB;Laird, PW
癌症中基因组不同部分的高甲基化和低甲基化如何相互关联以及与 DNA 甲基转移酶 (DNMT) 基因表达的关系尚不清楚。我们使用不同恶性潜能的卵巢上皮肿瘤来寻找 5' 基因区域或启动子高甲基化、卫星或整体 DNA 低甲基化以及 10 种 DNMT 亚型的 RNA 水平之间的关联。在定量 MethyLight 检测中，55 个检查基因位点中的 6 个（LTB4R、MTHFR、CDH13、PGR、CDH1 和 IGSF4）相对于恶性程度显着高甲基化（多重比较调整后；P < 0.001）。重要的是，这些基因的高甲基化与恶性程度相关，独立于卫星或整体DNA低甲基化与恶性程度的关联。只有两个研究基因 LTB4R 和 MTHFR 与癌症相关的甲基化增加与 DNMT1 RNA 水平相关，即使在对照组织中，这两个基因也明显甲基化。尽管与 ICF 综合征相关的 DNMT3B 缺陷导致近着丝粒卫星 DNA 低甲基化，但与癌症相关的卫星 DNA 低甲基化与所有 DNMT3B 同工型的 RNA 水平无关。我们的结果表明，癌症中的基因高甲基化与 DNMT RNA 水平改变之间并没有简单的关联，并且这种高甲基化既不是卫星 DNA 和整体 DNA 低甲基化的结果也不是原因。
How hypermethylation and hypomethylation of different parts of the genome in cancer are related to each other and to DNA methyltransferase ( DNMT) gene expression is ill defined. We used ovarian epithelial tumors of different malignant potential to look for associations between 5'-gene region or promoter hypermethylation, satellite, or global DNA hypomethylation, and RNA levels for ten DNMT isoforms. In the quantitative MethyLight assay, six of the 55 examined gene loci ( LTB4R, MTHFR, CDH13, PGR, CDH1, and IGSF4) were significantly hypermethylated relative to the degree of malignancy ( after adjustment for multiple comparisons; P < 0.001). Importantly, hypermethylation of these genes was associated with degree of malignancy independently of the association of satellite or global DNA hypomethylation with degree of malignancy. Cancer-related increases in methylation of only two studied genes, LTB4R and MTHFR, which were appreciably methylated even in control tissues, were associated with DNMT1 RNA levels. Cancer-linked satellite DNA hypomethylation was independent of RNA levels for all DNMT3B isoforms, despite the ICF syndrome-linked DNMT3B deficiency causing juxtacentromeric satellite DNA hypomethylation. Our results suggest that there is not a simple association of gene hypermethylation in cancer with altered DNMT RNA levels, and that this hypermethylation is neither the result nor the cause of satellite and global DNA hypomethylation.