Distinct genetic profiles in colorectal tumors with or without the CpG island methylator phenotype

被引:371
作者
Toyota, M
Ohe-Toyota, M
Ahuja, N
Issa, JPJ
机构
[1] Univ Texas, MD Anderson Canc Ctr, Dept Leukemia, Houston, TX 77030 USA
[2] Johns Hopkins Oncol Ctr, Baltimore, MD 21231 USA
关键词
D O I
10.1073/pnas.97.2.710
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
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.
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页码:710 / 715
页数:6
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