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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Transcriptionally repressed genes become aberrantly methylated and distinguish tumors of different lineages in breast cancer
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Transcriptionally repressed genes become aberrantly methylated and distinguish tumors of different lineages in breast cancer

机译：被转录抑制的基因异常甲基化并区分乳腺癌中不同谱系的肿瘤

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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.
机译：在癌症中经常观察到异常的启动子高甲基化。这种机制有助于肿瘤发展的潜力取决于受影响的基因是否由于其甲基化而被抑制。许多异常甲基化的基因在发育中起重要作用，并在ES细胞中被二价标记，表明它们的异常甲基化可能反映了发育过程。我们通过分析19个乳腺癌细胞系和47个原发性乳腺癌中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）有关的基因，这些基因被显着抑制。这些基因使细胞系无监督地分离成上皮（EPCAM + ve）和间充质（EPCAM-ve）谱系。然而，甲基化的基因已经在相同谱系的正常细胞中被阻遏，并且通过使用5-氮杂2'-脱氧胞苷处理不能使> 90％的阻抑。抑癌基因APC和CDH1以谱系特异性方式甲基化。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被异常甲基化，而在正常上皮细胞中特异性抑制的基因也是如此。 SRAM基因表达特征还正确地鉴定了具有间充质特征的罕见克劳丁低和化生性肿瘤。我们的发现暗示DNA甲基化异常是细胞谱系的标志物，而不是肿瘤进展的标志，并且表明在大多数情况下，它不会引起与之相关的抑制。

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    Duncan Sproul; Colm Nestor; Jayne Culley; Jacqueline H. Dickson; J. Michael Dixon; David J. Harrison; Richard R. Meehan; Andrew H. Sims; Bernard H. Ramsahoye;

  • 作者单位

    Breakthrough Breast Cancer Research Unit, Edinburgh EH4 2XU, United Kingdom Edinburgh Cancer Research Centre, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh EH4 2XU, United Kingdom;

    Breakthrough Breast Cancer Research Unit, Edinburgh EH4 2XU, United Kingdom Medical Research Council Human Genetics Unit, Institute of Genetics and Molecular Medicine, Edinburgh EH4 2XU, United Kingdom;

    Breakthrough Breast Cancer Research Unit, Edinburgh EH4 2XU, United Kingdom Edinburgh Cancer Research Centre, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh EH4 2XU, United Kingdom;

    Breakthrough Breast Cancer Research Unit, Edinburgh EH4 2XU, United Kingdom Edinburgh Cancer Research Centre, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh EH4 2XU, United Kingdom;

    Breakthrough Breast Cancer Research Unit, Edinburgh EH4 2XU, United Kingdom Edinburgh Breast Unit, Western General Hospital, Edinburgh EH4 2XU, United Kingdom;

    Breakthrough Breast Cancer Research Unit, Edinburgh EH4 2XU, United Kingdom;

    Breakthrough Breast Cancer Research Unit, Edinburgh EH4 2XU, United Kingdom Medical Research Council Human Genetics Unit, Institute of Genetics and Molecular Medicine, Edinburgh EH4 2XU, United Kingdom;

    Breakthrough Breast Cancer Research Unit, Edinburgh EH4 2XU, United Kingdom Edinburgh Cancer Research Centre, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh EH4 2XU, United Kingdom;

    Breakthrough Breast Cancer Research Unit, Edinburgh EH4 2XU, United Kingdom Edinburgh Cancer Research Centre, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh EH4 2XU, United Kingdom;

  • 收录信息 美国《科学引文索引》(SCI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
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