Abstract
Cancer cells display widespread genetic and epigenetic abnormalities, but the contribution to disease risk, particularly in normal tissue before disease, is not yet established. Genome-wide hypomethylation occurs frequently in tumors and may facilitate chromosome instability, aberrant transcription and transposable elements reactivation. Several epidemiologic case-control studies have reported genomic hypomethylation in peripheral blood of cancer patients, suggesting a systemic effect of hypomethylation on disease predisposition, which may be exploited for biomarker development. However, more recent studies have failed to reproduce this. Here, we report a meta-analysis, indicating a consistent inverse association between genomic 5-methylcytosine levels and cancer risk [95% confidence interval (CI), 1.2-6.1], but no overall risk association for studies using surrogates for genomic methylation, including methylation at the LINE-1 repetitive element (95% CI, 0.8-1.7). However, studies have been highly heterogeneous in terms of experimental design, assay type, and analytical methods. We discuss the limitations of the current approaches, including the low interindividual variability of surrogate assays such as LINE1 and the importance of using prospective studies to investigate DNA methylation in disease risk. Insights into genomic location of hypomethylation, from recent whole genome, high-resolution methylome maps, will help address this interesting and clinically important question.
Highlights
Epigenetics is the mitotically heritable control of gene expression and chromatin structure through covalent modification by DNA methylation, posttranslational modifications of histone proteins, and control of gene expression by noncoding RNAs [1, 2]
Epigenetic regulation is often studied in the context of environmental and population health, as widespread DNA methylation patterns are known to be affected by environmental, lifestyle, and demographic factors that affect complex disease risk, such as diet, carcinogen exposure, reproductive factors, and age [12, 13]
Widespread DNA methylation patterns can be measured using methylation sensitive restriction enzymes with relatively high resolution; methylation analysis is biased toward regions of high CpG density, as the enzyme restriction sites occur at sequences such as CCGG, and CGCG for the HpaII and Hha1 restriction enzymes, respectively [45, 74]
Summary
Epigenetics is the mitotically heritable control of gene expression and chromatin structure through covalent modification by DNA methylation, posttranslational modifications of histone proteins, and control of gene expression by noncoding RNAs [1, 2]. The first described cancer-associated epigenetic phenomenon was the lower net percentage of 5meC in tumor tissue compared with equivalent normal tissue, known as "genome-wide" or "global" hypomethylation, that occurs frequently in all cancer types [18, 19] Despite considerable research, it remains unclear whether promoter hypermethylation and genome-wide hypomethylation are mechanistically linked, or are independent processes. Genome-Wide Hypomethylation and Cancer Risk and Alu elements are heavily methylated in normal somatic tissue, hypomethylation of both, especially L1, is often detectable in tumors [20, 30, 49]. The studies investigating this, their findings, and the research approaches used, will be discussed further
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