Global DNA Hypomethylation (LINE-1) in the Normal Colon and Lifestyle Characteristics and Dietary and Genetic Factors

Abstract

Background: Global loss of methylated cytosines in DNA, thought to predispose to chromosomal instability and aneuploidy, has been associated with an increased risk of colorectal neoplasia. Little is known about the relationships between global hypomethylation and lifestyle, demographics, dietary measures, and genetic factors. Methods: Our data were collected as part of a randomized clinical trial testing the efficacy of aspirin and folic acid for the prevention of colorectal adenomas. At a surveillance colonoscopy f3 years after the qualifying exam, we obtained two biopsies of the normal-appearing mucosa from the right colon and two biopsies from the left colon. Specimens were assayed for global hypomethylation using a pyrosequencing assay for LINE-1 (long interspersed nucleotide elements) repeats. Results: The analysis included data from 388 subjects. There was relatively little variability in LINE meth-

DNA methylation within the normal colorectal mucosa is associated with pathway-specific predisposition to cancer

“…In our study, however, there was no association between LINE-1 methylation and concomitant pathology. This is consistent with the report by Figueiredo et al (2009).…”

“…The results are mixed. Some have reported no association with pathology, others that patients with polyps have increased methylation within their colorectal field and two recent reports have even suggested an inverse association between the presence of colorectal neoplasia and background mucosal methylation (Ye et al, 2006;Al-Ghnaniem et al, 2007;Belshaw et al, 2008;Horii et al, 2008;Ally et al, 2009;Figueiredo et al, 2009;Menigatti et al, 2009). Reconciling these discrepant results is limited by nonstandardized mucosal sampling, the important confounders of age and region, the use of variable marker panels and techniques and that adenomas may not be an adequate pathological end point when evaluating methylation markers more closely associated with the CIMP pathway.…”

Associations between genetic variation in one-carbon metabolism and LINE-1 DNA methylation in histologically normal breast tissues

“…In contrast, evidence from analysis of the association between the MTHFR A1298C SNP and genome-wide methylation in various sample types, indicates a null association. 17,[39][40][41][42] Although evidence from a recent meta-analysis also indicates no association between the MTHFR A1298C SNP and breast cancer risk, 43 this SNP has been found to be associated with both folate and homocysteine concentrations; 44,45 and the variant homozygous allele, specifically, is associated with lower enzymatic activity compared to the common genotype. 46 MTHFR is an important enzyme in the one-carbon metabolism pathway and the most frequently studied SNPs in this gene are C677T and A1298C, both reducing the enzyme activity in humans, albeit at different levels.…”

Gestational intake of methyl donors and global LINE-1 DNA methylation in maternal and cord blood: Prospective results from a folate-replete population

“…14,15 For example, Friso et al did not find an association between plasma folate and global genomic methylation in lymphocytes of 198 non-pregnant adults except among subjects with MTHFR minor variants, in whom low folate was associated with lower methylation. 15 There are several potential explanations for the lack of association of methyl donor intake with DNA methylation in our study.…”