Journal Article

Differential DNA hypermethylation and hypomethylation signatures in colorectal cancer

Jordi Frigola, Xavier Solé, Maria F. Paz, Victor Moreno, Manel Esteller, Gabriel Capellà and Miguel A. Peinado

in Human Molecular Genetics

Volume 14, issue 2, pages 319-326
Published in print January 2005 | ISSN: 0964-6906
Published online December 2004 | e-ISSN: 1460-2083 | DOI: http://dx.doi.org/10.1093/hmg/ddi028
Differential DNA hypermethylation and hypomethylation signatures in colorectal cancer

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Cancer cells are characterized by a generalized disruption of the DNA methylation pattern involving an overall decrease in the level of 5-methylcytosine together with regional hypermethylation of particular CpG islands. The extent of both DNA hypomethylation and hypermethylation in the tumor cell is likely to reflect distinctive biological and clinical features, although no studies have addressed its concurrent analysis until now. DNA methylation profiles in sporadic colorectal carcinomas, synchronous adenoma–carcinoma pairs and their matching normal mucosa were analyzed by using the amplification of inter-methylated sites (AIMS) method. A total of 208 AIMS generated sequences were tagged and evaluated for differential methylation. Global indices of hypermethylation and hypomethylation were calculated. All tumors displayed altered patterns of DNA methylation in reference to normal tissue. On average, 24% of the tagged sequences were differentially methylated in the tumor in regard to the normal pair with an overall prevalence of hypomethylations to hypermethylations. Carcinomas exhibited higher levels of hypermethylation than did adenomas but similar levels of hypomethylation. Indices of hypomethylation and hypermethylation showed independent correlations with patient's sex, tumor staging and specific gene hypermethylation. 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 and alternative correlates of hypomethylation and hypermethylation with survival. We conclude that DNA hypermethylation and hypomethylation are independent processes and appear to play different roles in colorectal tumor progression. Subgroups of colorectal tumors show specific genetic and epigenetic signatures and display distinctive correlates with overall survival.

Journal Article.  5366 words.  Illustrated.

Subjects: Genetics and Genomics

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