Distinct genetic profiles in colorectal tumors with or without the CpG island methylator phenotype
Distinct genetic profiles in colorectal tumors with or without the CpG island methylator phenotype
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DOI：
10.1073/pnas.97.2.710
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发表时间：
2000-01-18
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;Ohe-Toyota, M;Issa, JPJ
结直肠癌（CRC）的特征在于多个遗传（突变）和表观遗传（CpC岛甲基化）改变，但尚不清楚这些改变是否通过随机过程独立进化。我们最近描述了一种称为CRC中CpG岛甲基化表型（CIMP）的新途径，其特征在于多个CpG岛同时甲基化，包括几个已知基因，如p16，hMLH 1和THBS 1。我们现在已经研究了一组有或没有CIMP的结直肠肿瘤中K-RAS，p53，DPC 4和TGF β RII的突变，我们发现，CIMP定义了两组具有显著不同遗传病变的肿瘤：与CIMP-病例（14/47，30%，P = 0.0005）相比，CIMP+ CRC（28/41，68%）中发现频繁的K-RAS突变。CIMP阳性组p53基因突变率为24%（10/41），CIMP阴性组为60%（30/46）（P = 0.002）。CIMP、K-RAS突变和p53突变之间的这些相互作用在结直肠腺瘤中得以保留，表明它们发生在癌变的早期。每组中表观遗传和遗传改变的不同组合表明，癌基因的激活和肿瘤抑制基因的失活与癌症中产生分子多样性的潜在机制有关，而不是简单地在癌症发展过程中积累随机蛋白。
Colorectal cancers (CRCs) are characterized by multiple genetic (mutations) and epigenetic (CpC island methylation) alterations, but it is not known whether these evolve independently through stochastic processes. We have recently described a novel pathway termed CpG island methylator phenotype (CIMP) in CRC, which is characterized by the simultaneous methylation of multiple CpC islands, including several known genes, such as p16, hMLH1, and THBS1, We have now studied mutations in K-RAS, p53, DPC4, and TGF beta RII in a panel of colorectal tumors with or without CIMP, We find that CIMP defines two groups of tumors with significantly different genetic lesions: frequent K-RAS mutations were found in CIMP+ CRCs (28/41, 68%) compared with CIMP- cases (14/47, 30%, P = 0.0005). By contrast, p53 mutations were found in 24% (10/41) of CIMP+ CRCs vs. 60% (30/46) of CIMP- cases (P = 0.002), Both of these differences were independent of microsatellite instability. These interactions between CIMP, K-RAS mutations, and p53 mutations were preserved in colorectal adenomas, suggesting that they occur early in carcinogenesis. The distinct combinations of epigenetic and genetic alterations in each group suggest that activation of oncogenes and inactivation of tumor suppressor genes is related to the underlying mechanism of generating molecular diversity in cancer, rather than simply accumulate stochastically during cancer development.