title: Chromosomal instability correlates with genome-wide DNA demethylation in human primary colorectal cancers.
abstract: DNA hypomethylation is a common trait of colorectal cancer. Studies in tumor cell lines and animal models indicate that genome-wide demethylation may cause genetic instability and hence facilitate or accelerate tumor progression. Recent studies have shown that DNA hypomethylation precedes genomic damage in human gastrointestinal cancer, but the nature of this damage has not been clearly established. Here, we show a thorough analysis of DNA methylation and genetic alterations in two series of colorectal carcinomas. The extent of DNA demethylation but not of hypermethylation (both analyzed by amplification of intermethylated sites in near 200 independent sequences arbitrarily selected) correlated with the cumulated genomic damage assessed by two different techniques (arbitrarily primed PCR and comparative genomic hybridization). DNA hypomethylation-related instability was mainly of chromosomal nature and could be explained by a genome-wide effect rather than by the concurrence of the most prevalent genetic and epigenetic alterations. Moreover, the association of p53 mutations with genomic instability was secondary to DNA hypomethylation and the correlation between DNA hypomethylation and genomic instability was observed in tumors with and without mutation in the p53 gene. Our data support a direct link between genome-wide demethylation and chromosomal instability in human colorectal carcinogenesis and are consistent with the studies in model systems demonstrating a role of DNA demethylation in inducing chromosomal instability.
authors.affiliation: Institut d'Investigació Biomèdica de Bellvitge, L'Hospitalet, Barcelona, Catalonia, Spain.
authors.forename: Jairo
authors.initials: J
authors.lastname: Rodriguez
authors.forename: Jordi
authors.initials: J
authors.lastname: Frigola
authors.forename: Elisenda
authors.initials: E
authors.lastname: Vendrell
authors.forename: Rosa-Ana
authors.initials: RA
authors.lastname: Risques
authors.forename: Mario F
authors.initials: MF
authors.lastname: Fraga
authors.forename: Cristina
authors.initials: C
authors.lastname: Morales
authors.forename: Victor
authors.initials: V
authors.lastname: Moreno
authors.forename: Manel
authors.initials: M
authors.lastname: Esteller
authors.forename: Gabriel
authors.initials: G
authors.lastname: Capellà
authors.forename: Maria
authors.initials: M
authors.lastname: Ribas
authors.forename: Miguel A
authors.initials: MA
authors.lastname: Peinado
mesh_terms: D043171:Chromosomal Instability; D002877:Chromosomes, Human / Q000235:genetics; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000473:pathology; D004249:DNA Damage; D019175:DNA Methylation; D004273:DNA, Neoplasm / Q000235:genetics*; D005784:Gene Amplification; D015894:Genome, Human; D006801:Humans; D008677:Metaphase; D009367:Neoplasm Staging; D009693:Nucleic Acid Hybridization
chemical_list: D004273:DNA, Neoplasm