Homeobox gene methylation in lung cancer studied by genome-wide analysis with a microarray-based methylated CpG island recovery assay
Homeobox gene methylation in lung cancer studied by genome-wide analysis with a microarray-based methylated CpG island recovery assay
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DOI：
10.1073/pnas.0701059104
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发表时间：
2007-03-27
影响因子：
11.1
通讯作者：
Pfeifer, Gerd P.
中科院分区：
文献类型：
--
作者：
Rauch, Tibor;Wang, Zunde;Pfeifer, Gerd P.
但与癌症相关的DNA甲基化机制尚不清楚。我们使用瓦片阵列结合甲基化CpG岛恢复测定，以高分辨率研究全基因组CpG岛的甲基化。我们发现，在癌细胞系和早期肺癌中，染色体2、7、12和17上的所有四个HOX基因簇都是DNA甲基化的优先靶点。与SIX、LHX、PAX、DLX和Engrailed等其他同源盒基因相关的CpG岛也高度甲基化。总的来说，肺癌细胞系A549中超过一半（192个中的104个）的CpG岛相关同源盒基因被甲基化。对同源HOX基因的分析表明，并非所有同源HOX基因同时发生与癌症相关的甲基化。对HOXA簇进行了更详细的分析。与encode数据的比较表明，在富含cpg的序列中缺乏甲基化与HOXA区域中存在活性染色质标记组蛋白H3赖氨酸-4甲基化相关。对原发性肺鳞状细胞癌中HOXA基因的甲基化分析发现，HOXA7-和hoxa9相关的CpG岛是1期肿瘤中常见的甲基化靶点。同型盒型基因作为DNA甲基化标记对疾病的早期诊断有潜在的作用。同源盒基因广泛甲基化的发现支持了一种假设，即人类癌症中相当一部分甲基化的基因是Polycomb复合物的目标。
human cancer, but the mechanisms of cancer-associated DNA methylation are not known. We have used tiling arrays in combination with the methylated CpG island recovery assay to investigate methylation of CpG islands genome-wide and at high resolution. We find that all four HOX gene clusters on chromosomes 2, 7,12, and 17 are preferential targets for DNA methylation in cancer cell lines and in early-stage lung cancer. CpG islands associated with many other homeobox genes, such as SIX, LHX, PAX, DLX, and Engrailed, were highly methylated as well. Altogether, more than half (104 of 192) of all CpG island-associated homeobox genes in the lung cancer cell line A549 were methylated. Analysis of paralogous HOX genes showed that not all paralogues undergo cancer-associated methylation simultaneously. The HOXA cluster was analyzed in greater detail. Comparison with ENCODE-derived data shows that lack of methylation at CpG-rich sequences correlates with presence of the active chromatin mark, histone H3 lysine-4 methylation in the HOXA region. Methylation analysis of HOXA genes in primary squamous cell carcinomas of the lung led to the identification of the HOXA7- and HOXA9-associated CpG islands as frequent methylation targets in stage 1 tumors. Homeobox genes are potentially useful as DNA methylation markers for early diagnosis of the disease. The finding of widespread methylation of homeobox genes lends support to the hypothesis that a substantial fraction of genes methylated in human cancer are targets of the Polycomb complex.