A gene hypermethylation profile of human cancer.
A gene hypermethylation profile of human cancer.
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发表时间：
2001-04
期刊：
影响因子：
11.2
通讯作者：
M. Esteller;M. Esteller;P. Corn;S. Baylin;J. Herman
中科院分区：
文献类型：
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作者：
M. Esteller;M. Esteller;P. Corn;S. Baylin;J. Herman
我们所处的时代，有可能获得表征每种形式人类癌症的DNA改变的综合概况。这些图谱将为了解每种肿瘤类型的演变机制提供宝贵的见解，并将提供分子标记物，这可以从根本上改善癌症检测。到目前为止，还没有一种类型的DNA变化被定义来实现这一目的。在这里，通过使用候选基因的方法，我们表明，一类DNA改变，基因启动子区域的异常甲基化，可以极大地促进上述目标。我们现在已经分析了12个基因（p16（INK 4a），p15（INK 4 b），p14（ARF），p73，APC，（5）BRCA 1，hMLH 1，GSTP 1，MGMT，CDH 1，TIMP 3和DAPK）的一系列启动子超甲基化变化，每个基因都被严格表征为与癌症中的异常基因沉默相关，这些基因来自代表15种主要肿瘤类型的600多个原发性肿瘤样本的DNA。这些基因在包括肿瘤抑制、细胞周期调节、细胞凋亡、DNA修复和肿瘤潜能的过程中发挥已知的重要作用。每种人类癌症都存在独特的启动子超甲基化谱，其中一些基因变化是共享的，而另一些则是癌症类型特异性的。基因的超甲基化独立地发生，以至于一组三到四个标记物在每种癌症类型的70-90%中定义异常。我们的研究结果提供了一个不寻常的观点，DNA改变的普遍性，在这种情况下，表观遗传学的变化，在人类癌症和一组强大的标志物，概述了在肿瘤发生的关键途径的破坏和衍生的敏感的分子检测策略，几乎每一个人类肿瘤类型。
We are in an era where the potential exists for deriving comprehensive profiles of DNA alterations characterizing each form of human cancer. Such profiles would provide invaluable insight into mechanisms underlying the evolution of each tumor type and will provide molecular markers, which could radically improve cancer detection. To date, no one type of DNA change has been defined which accomplishes this purpose. Herein, by using a candidate gene approach, we show that one category of DNA alteration, aberrant methylation of gene promoter regions, can enormously contribute to the above goals. We have now analyzed a series of promoter hypermethylation changes in 12 genes (p16(INK4a), p15(INK4b), p14(ARF), p73, APC,(5) BRCA1, hMLH1, GSTP1, MGMT, CDH1, TIMP3, and DAPK), each rigorously characterized for association with abnormal gene silencing in cancer, in DNA from over 600 primary tumor samples representing 15 major tumor types. The genes play known important roles in processes encompassing tumor suppression, cell cycle regulation, apoptosis, DNA repair, and metastastic potential. A unique profile of promoter hypermethylation exists for each human cancer in which some gene changes are shared and others are cancer-type specific. The hypermethylation of the genes occurs independently to the extent that a panel of three to four markers defines an abnormality in 70-90% of each cancer type. Our results provide an unusual view of the pervasiveness of DNA alterations, in this case an epigenetic change, in human cancer and a powerful set of markers to outline the disruption of critical pathways in tumorigenesis and for derivation of sensitive molecular detection strategies for virtually every human tumor type.