Abstract
BackgroundThe methylation of DNA is recognized as a key epigenetic mechanism and evidence for its role in the development of several malignancies is accumulating. We evaluated the relationship between global methylation in DNA derived from normal appearing colon mucosal tissue and blood leukocytes, and colorectal adenoma risk.MethodsPatients, aged 40 to 65, scheduled for a screening colonoscopy were recruited. During the colonoscopy, two pinch biopsies of healthy, normal appearing mucosa were obtained from the descending colon. A fasting blood sample was also collected. The methylation status of LINE-1 (long interspersed nuclear element-1) repetitive sequences, as a surrogate measure of global methylation, was quantified in DNA extracted from normal colon mucosa and blood leukocytes. Statistical analysis of the relationship between global DNA methylation and adenoma risk was conducted on 317 participants, 108 subjects with at least one pathologically confirmed adenoma and 209 subjects with a normal colonoscopy.ResultsA statistically significant inverse relationship was observed between LINE-1 methylation in colon tissue DNA and adenoma risk for males and for both sexes combined for the lowest methylation quartile compared to the highest (adjusted ORs = 2.94 and 2.26 respectively). For blood, although the overall pattern of odds ratio estimates was towards an increase in risk for lower methylation quartiles compared to the highest methylation quartile, there were no statistically significant relationships observed. A moderate correlation was found between LINE-1 methylation levels measured in tissue and blood (Pearson correlation 0.36).ConclusionsWe observed that lower levels of LINE-1 DNA methylation in normal appearing background colon mucosa were associated with increased adenoma risk for males, and for both sexes combined. Though these findings provide some support for a relationship between LINE-1 DNA methylation in colon mucosal tissue and adenoma risk, large prospective cohort studies are needed to confirm results. Until such investigations are done, the clinical usefulness of LINE-1 methylation as a biomarker of increased adenoma risk is uncertain. Regardless, this study contributes to a better understanding of the role of global DNA methylation as an early event in CR carcinogenesis with implications for future etiologic research.
Highlights
The methylation of DNA is recognized as a key epigenetic mechanism and evidence for its role in the development of several malignancies is accumulating
Those diagnosed with IBD or colorectal cancer based on current colonoscopy findings were excluded from the final study population as it was a concern that global DNA methylation levels in these patients may not be consistent with the target time period of interest
Our results indicating that LINE1 DNA hypomethylation in normal appearing colon mucosa is associated with increased adenoma risk, suggest that aberrant global hypomethylation in healthy background colon mucosa represents an underlying pervasive epigenetic aberration, often referred to as a ‘field defect’, which may confer an increased predisposition to the development of colorectal adenomas/cancer [46,67,68,69,70]
Summary
The methylation of DNA is recognized as a key epigenetic mechanism and evidence for its role in the development of several malignancies is accumulating. There is wide-spread interest in clarifying the role of aberrant global DNA methylation as an early event in colorectal carcinogenesis. The methylation of DNA is recognized as a key epigenetic mechanism in the regulation of gene expression and chromosomal stability, and evidence for its role in the development of several malignancies is accumulating [10,11,12]. LINE-1 (long interspersed nuclear element-1) sequences, with an average size of 900 base pairs, comprise approximately 17% of the human genome [16] and are the most widely studied repetitive sequence within the context of global DNA methylation measurement [17,18]. LINE-1 methylation levels have been shown to represent a reliable surrogate measure of global DNA methylation [19,20,21,22,23]
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