Kim Yong Ho, Kakar Sanjay, Cun Lisa, Deng Guoren, Kim Young S
Gastrointestinal Research Laboratory (151M2), Veterans Affairs Medical Center, San Francisco, CA 94121, USA.
Int J Cancer. 2008 Dec 1;123(11):2587-93. doi: 10.1002/ijc.23840.
A subset of colorectal cancers with CpG island methylator phenotype-high (CIMP-H) is frequently associated with MSI and BRAF V600E mutation. Since limited data are available on different histological types of colorectal polyps, we compared the pattern and the frequency of promoter methylation, CIMP-H, MSI, KRAS and BRAF V600E mutations and the relationship among these molecular parameters and the clinicopathologic characteristics in 110 serrated polyps (48 hyperplastic polyps, 32 sessile serrated adenomas and 30 serrated adenomas) and 32 tubular adenomas using 7 commonly used tumor-associated gene loci. No significant difference in the frequency of overall methylation frequency (86% vs. 100%) and CIMP-H (39% vs. 28%) between serrated polyps and tubular adenomas was observed, but proximally located serrated polyps showed more frequent methylation at 5 of 7 loci examined, and were more likely to be CIMP-H (62% vs. 22%). MGMT methylation was more common in tubular adenomas while MLH1 and HIC1 were more frequently methylated in serrated polyps. BRAF mutation was frequently present in all types of serrated polyps (80%), but was absent in tubular adenomas and was not associated with CIMP or MSI status. These results show comparable frequencies of promoter methylation of tumor-associated genes and CIMP-H, but distinct differences in gene-specific or colonic site-specific methylation profiles occur in serrated polyps and tubular adenomas. BRAF mutation occurs independently of CIMP and MSI in all types of serrated polyps and may serve as a marker of serrated pathway of colorectal carcinogenesis.
具有CpG岛甲基化表型高（CIMP-H）的一部分结直肠癌常与微卫星高度不稳定（MSI）和BRAF V600E突变相关。由于关于不同组织学类型的大肠息肉的可用数据有限，我们使用7个常用的肿瘤相关基因位点，比较了110个锯齿状息肉（48个增生性息肉、32个无蒂锯齿状腺瘤和30个锯齿状腺瘤）和32个管状腺瘤中启动子甲基化模式和频率、CIMP-H、MSI、KRAS和BRAF V600E突变以及这些分子参数与临床病理特征之间的关系。锯齿状息肉和管状腺瘤之间在总体甲基化频率（86%对100%）和CIMP-H（39%对28%）频率上未观察到显著差异，但近端的锯齿状息肉在7个检测位点中的5个显示出更频繁的甲基化，并且更可能是CIMP-H（62%对22%）。MGMT甲基化在管状腺瘤中更常见，而MLH1和HIC1在锯齿状息肉中更频繁地甲基化。BRAF突变在所有类型的锯齿状息肉中经常出现（80%），但在管状腺瘤中不存在，并且与CIMP或MSI状态无关。这些结果表明肿瘤相关基因启动子甲基化和CIMP-H的频率相当，但锯齿状息肉和管状腺瘤在基因特异性或结肠部位特异性甲基化谱方面存在明显差异。BRAF突变在所有类型的锯齿状息肉中独立于CIMP和MSI发生，并且可能作为结直肠癌发生锯齿状途径的标志物。
