Profiles of DNA methylation in colorectal cancer

3728 Background: DNA methylation profiles in cancer cells are characterized by an overall decrease in the level of 5-methylcytosine and regional hypermethylation on particular CpG islands. We have addressed the concurrent study of DNA hyper- and hypomethylation and the analysis of its possible correlates with other features in a series of human colorectal cancers. Methods: DNA methylation profiles in sporadic colorectal carcinomas (n=98), synchronous adenoma-carcinoma pairs (n=11) and their paired normal mucosa were analyzed by using the Amplification of Inter-Methylated Sites (AIMS) method. A total of 208 anonymous methylated tags were evaluated for differential methylation. Global indices of hyper- and hypomethylation were calculated. Also MSI, K-ras, p53 mutations and hypermethylation at specific genes were assessed. Results: All adenomas and carcinomas displayed altered patterns of DNA methylation in reference to the normal tissue. In average, 24% of the represented tags were differentially methylated in carcinomas in regard to the normal pair with an overall prevalence of hypomethylations (14.6%) to hypermethylations (9.6%). Carcinomas exhibited higher (9.6%) levels of hypermethylation than adenomas (7.1%) but similar levels of hypomethylation. Hypermethylation correlated with female sex, advanced tumor stage and number of hypermethylated genes. Hierarchical cluster analysis revealed two main patterns of DNA methylation that were associated to particular mutational spectra in the K-ras and the p53 genes. In both groups correlates of hypomethylation or hypermethylation with survival were observed. Discussion: DNA hypermethylation and hypomethylation appear to play different roles in colorectal tumor progression and correlate with overall survival in subgroups with specific genetic and epigenetic signatures. No significant financial relationships to disclose.