Characteristic methylation profile in CpG island methylator phenotype-negative distal colorectal cancers
Characteristic methylation profile in CpG island methylator phenotype-negative distal colorectal cancers
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DOI：
10.1002/ijc.25225
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发表时间：
2010-11-01
影响因子：
6.4
通讯作者：
Sekido, Yoshitaka
中科院分区：
文献类型：
--
作者：
An, Byonggu;Kondo, Yutaka;Sekido, Yoshitaka
异常DNA甲基化参与结肠癌的发生。尽管CpG岛甲基化表型（CIMP）被定义为具有显著高水平DNA甲基化的结直肠癌（crc）的一个子集，但尚不清楚表观遗传过程是否也参与CIMP阴性肿瘤。我们用11种不同的标记分析了94种crc及其相应的正常结肠粘膜的DNA甲基化谱，其中包括5种经典的CIMP标记。CIMP标记在近端crc中频繁甲基化（p < 0.01）；然而，RASSF1A甲基化水平在远端crc中显著较高，其中大多数为cimp阴性（p < 0.05）。同样，远端CRC正常粘膜中RASSF1A和SFRP1的甲基化水平显著高于近端CRC患者（p < 0.05）。与年龄呈正相关（RASSF1A, p < 0.01; SFRP1, p < 0.01）。基于微阵列的18个crc全基因组DNA甲基化分析显示，在cimp阴性的远端crc和cimp阳性的crc中，分别有168个基因和720个基因优先甲基化。有趣的是，在cimp阴性的远端crc中，超过一半的高甲基化基因也在正常出现的粘膜中甲基化，这表明cimp阴性的远端crc中的高甲基化与年龄相关的甲基化更密切相关。相比之下，cimp阳性的近端crc中超过60%的高甲基化基因是癌症特异性的（p < 0.01）。这些数据表明，CpG岛启动子似乎在不同的位置以不同的方式甲基化，这一发现可能意味着在结肠肿瘤发生过程中存在不同的获得表观遗传变化的机制。
Aberrant DNA methylation is involved in colon carcinogenesis. Although the CpG island methylator phenotype (CIMP) is defined as a subset of colorectal cancers (CRCs) with remarkably high levels of DNA methylation, it is not known whether epigenetic processes are also involved in CIMP-negative tumors. We analyzed the DNA methylation profiles of 94 CRCs and their corresponding normal appearing colonic mucosa with 11 different markers, including the five classical CIMP markers. The CIMP markers were frequently methylated in proximal CRCs (p < 0.01); however, RASSF1A methylation levels were significantly higher in distal CRCs, the majority of which are CIMP-negative (p < 0.05). Similarly, methylation levels of RASSF1A and SFRP1 in the normal-appearing mucosae of distal CRC cases were significantly higher than those in the proximal CRC cases (p < 0.05). They were also positively correlated with age (RASSF1A, p < 0.01; SFRP1, p < 0.01). Microarray-based genome-wide DNA methylation analysis of 18 CRCs revealed that 168 genes and 720 genes were preferentially methylated in CIMP-negative distal CRCs and CIMP-positive CRCs, respectively. Interestingly, more than half of the hypermethylated genes in CIMP-negative distal CRCs were also methylated in the normal appearing mucosae, indicating that hypermethylation in CIMP-negative distal CRCs is more closely associated with age related methylation. By contrast, more than 60% of the hypermethylated genes in CIMP-positive proximal CRCs were cancer specific (p < 0.01). These data altogether suggest that CpG island promoters appear to be methylated in different ways depending on location, a finding which may imply the presence of different mechanisms for the acquisition of epigenetic changes during colon tumorigenesis.