Transcriptionally repressed genes become aberrantly methylated and distinguish tumors of different lineages in breast cancer
Transcriptionally repressed genes become aberrantly methylated and distinguish tumors of different lineages in breast cancer
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DOI：
10.1073/pnas.1013224108
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发表时间：
2011-03-15
影响因子：
11.1
通讯作者：
Ramsahoye, Bernard H.
中科院分区：
文献类型：
--
作者：
Sproul, Duncan;Nestor, Colm;Ramsahoye, Bernard H.
异常启动子高甲基化在癌症中经常观察到。这种机制促进肿瘤发展的潜力取决于受影响的基因是否因其甲基化而受到抑制。许多异常甲基化的基因在发育中起重要作用，并且在ES细胞中是生物标记的，这表明它们的异常甲基化可能反映发育过程。我们通过分析19个乳腺癌细胞系和47个原发性乳腺肿瘤的启动子甲基化来研究这种可能性。在细胞系中，我们定义了120个与甲基化（SRAM）相关的显著抑制基因。这些基因允许细胞系在无监督的情况下分离成上皮（EPCAM+ve）和间充质（EPCAM-ve）谱系。然而，甲基化基因在相同谱系的正常细胞中已经被抑制，并且> 90%不能通过5-氮杂-2 '-脱氧胞苷处理而被去抑制。肿瘤抑制基因APC和CDH 1是以谱系特异性方式甲基化的基因之一。正如大多数乳腺肿瘤的上皮性质所预测的那样，在上皮细胞系中甲基化的SRAM基因在原发性肿瘤中经常异常甲基化，就像在正常上皮细胞中特异性抑制的基因一样。SRAM基因表达特征也正确鉴定了罕见的低密蛋白和化生性肿瘤具有间质特征。我们的研究结果暗示异常DNA甲基化是细胞谱系的标志，而不是肿瘤进展，并表明在大多数情况下，它不会引起与之相关的抑制。
Aberrant promoter hypermethylation is frequently observed in cancer. The potential for this mechanism to contribute to tumor development depends on whether the genes affected are repressed because of their methylation. Many aberrantly methylated genes play important roles in development and are bivalently marked in ES cells, suggesting that their aberrant methylation may reflect developmental processes. We investigated this possibility by analyzing promoter methylation in 19 breast cancer cell lines and 47 primary breast tumors. In cell lines, we defined 120 genes that were significantly repressed in association with methylation (SRAM). These genes allowed the unsupervised segregation of cell lines into epithelial (EPCAM+ve) and mesenchymal (EPCAM-ve) lineages. However, the methylated genes were already repressed in normal cells of the same lineage, and > 90% could not be derepressed by treatment with 5-aza-2'-deoxycytidine. The tumor suppressor genes APC and CDH1 were among those methylated in a lineage-specific fashion. As predicted by the epithelial nature of most breast tumors, SRAM genes that were methylated in epithelial cell lines were frequently aberrantly methylated in primary tumors, as were genes specifically repressed in normal epithelial cells. An SRAM gene expression signature also correctly identified the rare claudin-low and metaplastic tumors as having mesenchymal characteristics. Our findings implicate aberrant DNA methylation as a marker of cell lineage rather than tumor progression and suggest that, in most cases, it does not cause the repression with which it is associated.