CpG island methylator phenotype in colorectal cancer
CpG island methylator phenotype in colorectal cancer
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DOI：
10.1073/pnas.96.15.8681
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发表时间：
1999-07-20
影响因子：
11.1
通讯作者：
Issa, JPJ
中科院分区：
文献类型：
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作者：
Toyota, M;Ahuja, N;Issa, JPJ
启动子区域 CPG 岛的异常甲基化与肿瘤中肿瘤抑制基因的转录失活有关。为了了解结直肠癌中 CpG 岛甲基化的整体模式，我们使用了最近开发的称为甲基化 CpG 岛扩增的技术来检查 30 个新克隆的差异甲基化 DNA 序列。在这30个克隆中，19个（63％）在正常结肠中以年龄依赖性方式逐渐甲基化，7个（23％）以癌症特异性方式甲基化，3个（13％）仅在细胞系中甲基化。因此，结肠癌中甲基化的大多数CpG岛在衰老过程中也在正常结肠细胞的子集中甲基化。相比之下，癌症特异性克隆的甲基化仅在细胞系中甲基化。结直肠癌似乎表现出 CpG 岛甲基化表型 (CIMP)，CIMP+ 肿瘤也具有高 p16 和 THBS1 甲基化发生率，并且它们包括大多数具有与 hMLH1 甲基化相关的微卫星不稳定性的散发性结直肠癌，因此我们定义了结直肠癌中的一条途径，该途径似乎是大多数具有错配修复缺陷的散发性肿瘤的原因。
Aberrant methylation of promoter region CPG islands is associated with transcriptional inactivation of tumor-suppressor genes in neoplasia, To understand global patterns of CpG island methylation in colorectal cancer, we have used a recently developed technique called methylated CpG island amplification to examine 30 newly cloned differentially methylated DNA sequences. Of these 30 clones, 19 (63%) were progressively methylated in an age-dependent manner in normal colon, 7 (23%) were methylated in a cancer-specific manner, and 3 (13%) were methylated only in cell lines, Thus, a majority of CpG islands methylated in colon cancer are also methylated in a subset of normal colonic cells during the process of aging, In contrast, methylation of the cancer-specific clones was Pound exclusively in a subset of colorectal cancers, which appear to display a CpG island methylator phenotype (CIMP), CIMP+ tumors also have a high incidence of p16 and THBS1 methylation, and they include the majority of sporadic colorectal cancers with microsatellite instability related to hMLH1 methylation, We thus define a pathway in colorectal cancer that appears to be responsible for the majority of sporadic tumors with mismatch repair deficiency.