Laboratory of Clinical Chemistry, University of Ioannina Medical School, 45500 Ioannina, Greece.
World J Gastroenterol. 2010 Jul 28;16(28):3553-60. doi: 10.3748/wjg.v16.i28.3553.
To investigate aberrant DNA methylation of CpG islands and subsequent low- or high-level DNA microsatellite instability (MSI) which is assumed to drive colon carcinogenesis.
DNA of healthy individuals, adenoma (tubular or villous/tubulovillous) patients, and colorectal carcinoma patients who underwent colonoscopy was used for assessing the prevalence of aberrant DNA methylation of human DNA mismatch repair gene mutator L homologue 1 (hMLH1), Cyclin-dependent kinase inhibitor 2A (CDKN2A/p16), and O-6-methylguanine DNA methyltransferase (MGMT), as well as their relation to MSI.
The frequency of promoter methylation for each locus increased in the sequence healthy tissue/adenoma/carcinoma. MGMT showed the highest frequency in each group. MGMT and CDKN2A/p16 presented a statistically significant increase in promoter methylation between the less and more tumorigenic forms of colorectal adenomas (tubular vs tubullovillous and villous adenomas). All patients with tubulovillous/villous adenomas, as well as all colorectal cancer patients, showed promoter methylation in at least one of the examined loci. These findings suggest a potentially crucial role for methylation in the polyp/adenoma to cancer progression in colorectal carcinogenesis. MSI and methylation seem to be interdependent, as simultaneous hMLH1, CDKN2A/p16, and MGMT promoter methylation was present in 8/9 colorectal cancer patients showing the MSI phenotype.
Methylation analysis of hMLH1, CDKN2A/p16, and MGMT revealed specific methylation profiles for tubular adenomas, tubulovillous/villous adenomas, and colorectal cancers, supporting the use of these alterations in assessment of colorectal tumorigenesis.
研究 CpG 岛的异常 DNA 甲基化及其随后的低水平或高水平 DNA 微卫星不稳定性（MSI），这被认为是导致结肠癌发生的原因。
使用结肠镜检查的健康个体、腺瘤（管状或绒毛状/管状绒毛状）患者和结直肠癌患者的 DNA，评估人错配修复基因突变易位 L 同源物 1（hMLH1）、细胞周期蛋白依赖性激酶抑制剂 2A（CDKN2A/p16）和 O-6-甲基鸟嘌呤 DNA 甲基转移酶（MGMT）的异常 DNA 甲基化的发生率，以及它们与 MSI 的关系。
每个基因座的启动子甲基化频率在健康组织/腺瘤/癌组织中依次增加。MGMT 在每个组中的频率最高。MGMT 和 CDKN2A/p16 在结直肠腺瘤（管状与管状绒毛状和绒毛状腺瘤）的肿瘤形成能力较弱和较强形式之间，其启动子甲基化呈统计学显著增加。所有管状绒毛状/绒毛状腺瘤以及所有结直肠癌患者均至少在一个检测基因座中显示启动子甲基化。这些发现提示甲基化在结直肠肿瘤发生中可能在息肉/腺瘤向癌症进展中起关键作用。MSI 和甲基化似乎是相互依赖的，因为 9 例 MSI 表型的结直肠癌患者中同时存在 hMLH1、CDKN2A/p16 和 MGMT 启动子甲基化。
hMLH1、CDKN2A/p16 和 MGMT 的甲基化分析显示出管状腺瘤、管状绒毛状/绒毛状腺瘤和结直肠癌的特定甲基化谱，支持这些改变用于评估结直肠肿瘤发生。
