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. (Cancer Res 2006; 66(17): 8462-8)

Real-time dynamics of methyl-CpG-binding domain protein 3 and its role in DNA demethylation by fluorescence correlation spectroscopy

“…Previously, most of the cancerous hypomethylation were found in short and long interspersed nuclear elements (SINEs and LINEs) and other repeat genomic regions, which were long-thought to be the noncoding junk DNA. 20,[67][68][69][70][71] With the release of the Encyclopedia of DNA Elements (ENCODE) data, nearly 80% of the human genome were found to be useful and could be assigned specific biochemical functions necessitating careful interrogation of the epigenetic state at these regions. 72 Considering the fact that the hypomethylated site varies among different cancers, an emerging thought is to study DNA demethylation in a locus-specific manner upon mutagenic stimulation so that targeted therapeutic strategies can be developed depending upon the type and state of the disease.…”

Differences in methylation profiles between HPV-positive and HPV-negative oropharynx squamous cell carcinoma

“…This is frequently seen in various types of cancer and is correlated with chromosomal instability. 12,64 Three studies showed a significant increase in hypomethylation of LINE-1 elements in HPV-negative tumors, [38][39][40] while Furniss et al found no association between LINE-1 methylation and HPV status. 32 This could be explained by differences in use of methylation assay and study population.…”

ALU and LINE‐1 hypomethylations in multistep gastric carcinogenesis and their prognostic implications

“…Promoter CpG island hypermethylation is an important mechanism that inactivates tumor suppressor and tumor-related genes; meanwhile, generalized genomic hypomethylation contributes to genomic or chromosomal instability. [1][2][3] Genomic hypomethylation mainly affects repetitive transposable DNA elements, which comprise 45% of the human genome 4 ; these elements reside mainly in the intergenic and intronic regions of the genome and in noncoding and coding exons of the genome to a much lesser extent. 5 Long interspersed nucleotide element-1 (LINE-1) and ALU are major constituents of interspersed DNA repeats, constituting $17% and 11% of the human genome, respectively.…”