Distinct genetic profiles in colorectal tumors with or 9enetic profiles in colorectal tumors with or without the CpG island methylator phenotype

摘要

Colorectal cancers (CRCs) are characterized by multiple genetic (mutations) and epigenetic (CpG 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 (ClMP) in CRC, which is characterized by the simultaneous methylation of multiple CpG islands, including several known genes, such as p16. hMLHf. and THBS1. We have now studied mutations in K-RAS, p53, DPC4, and TGFpRII in a panel of colorectal tumors with or without CIMP. We find that CIMP defines two groups of tumors with significantly different genetic Iesions: frequent K-RAS mutations were found in ClMP~+ CRCs (28/41, 68/100) compared with ClMP-- cases (14/47, 30/100. P = 0.0005). By contrast, p~53 mutations were found in 24/100 (10/41) of CIMP~+ CRCs vs. 60/100 (30/46) of CIMP-- cases (P = 0.002). Both of these differences were independent of microsatellite instability. These interactions between ClMP. K-RAS mutations, and p~53 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 mo- lecular diversity in cancer. rather than simply accumulate stochas- tically during cancer development.