Weisenberger Daniel J, Siegmund Kimberly D, Campan Mihaela, Young Joanne, Long Tiffany I, Faasse Mark A, Kang Gyeong Hoon, Widschwendter Martin, Weener Deborah, Buchanan Daniel, Koh Hoey, Simms Lisa, Barker Melissa, Leggett Barbara, Levine Joan, Kim Myungjin, French Amy J, Thibodeau Stephen N, Jass Jeremy, Haile Robert, Laird Peter W
Department of Surgery, University of Southern California/Norris Comprehensive Cancer Center, Los Angeles, California 90089-9176, USA.
Nat Genet. 2006 Jul;38(7):787-93. doi: 10.1038/ng1834. Epub 2006 Jun 25.
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'. However, the existence of CIMP has been challenged. 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.
CpG岛的异常DNA甲基化在人类结肠直肠肿瘤中广泛存在，当其发生在启动子区域时与基因沉默相关。一部分结肠直肠肿瘤中某些CpG岛的甲基化频率异常高，这提示了一种被称为“CpG岛甲基化表型”或“CIMP”的独特特征。然而，CIMP的存在受到了质疑。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、逐步的筛选，涉及295例原发性人类结肠直肠肿瘤和16785次独立的定量分析。我们发现，CIMP阳性（CIMP+）肿瘤确实代表了一个独特的亚组，几乎涵盖了所有BRAF突变的肿瘤病例（优势比=203）。错配修复缺陷的散发病例几乎完全是由于MLH1的CIMP相关甲基化所致。我们提出了一个强大的新标记物组合来对CIMP+肿瘤进行分类。
