CpG island methylator phenotype underlies sporadic microsatellite instability and is tightly associated with BRAF mutation in colorectal cancer
CpG island methylator phenotype underlies sporadic microsatellite instability and is tightly associated with BRAF mutation in colorectal cancer
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DOI：
10.1038/ng1834
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发表时间：
2006-07-01
期刊：
影响因子：
30.8
通讯作者：
Laird, Peter W.
中科院分区：
文献类型：
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作者：
Weisenberger, Daniel J.;D Siegmund, Kimberly;Laird, Peter W.
CpG岛的异常甲基化在人类结直肠肿瘤中已被广泛观察到，并且当其发生在启动子区域时与基因沉默相关。结直肠肿瘤的一个亚组具有异常高的某些CpG岛甲基化频率，导致被称为“CpG岛甲基化表型”或“CIMP”的独特性状的建议（1，2）。然而，CIMP的存在受到了质疑（3，4）。为了解决这一持续的争议，我们使用MethyLight技术对195个CpG岛甲基化标记物进行了系统的逐步筛选，涉及295个原发性人类结直肠肿瘤和16，785个单独的定量分析。我们发现，CIMP阳性（CIMP+）肿瘤令人信服地代表了一个独特的子集，几乎涵盖了所有BRAF突变的肿瘤病例（优势比= 203）。错配修复缺陷的零星病例几乎完全是由于CMP相关的MLH1甲基化而发生的。我们提出了一个强大的新的标志物面板分类CIMP+肿瘤。
Aberrant DNA methylation of CpG islands has been widely observed in human colorectal tumors and is associated with gene silencing when it occurs in promoter areas. A subset of colorectal tumors has an exceptionally high frequency of methylation of some CpG islands, leading to the suggestion of a distinct trait referred to as 'CpG island methylator phenotype', or 'CIMP'(1,2). However, the existence of CIMP has been challenged(3,4). To resolve this continuing controversy, we conducted a systematic, stepwise screen of 195 CpG island methylation markers using MethyLight technology, involving 295 primary human colorectal tumors and 16,785 separate quantitative analyses. We found that CIMP-positive (CIMP+) tumors convincingly represent a distinct subset, encompassing almost all cases of tumors with BRAF mutation (odds ratio = 203). Sporadic cases of mismatch repair deficiency occur almost exclusively as a consequence of CIMP-associated methylation of MLH1. We propose a robust new marker panel to classify CIMP+ tumors.