LINE-1 Hypomethylation in Blood and Tissue Samples as an Epigenetic Marker for Cancer Risk: A Systematic Review and Meta-Analysis

Abstract

ObjectiveA systematic review and a meta-analysis were carried out in order to summarize the current published studies and to evaluate LINE-1 hypomethylation in blood and other tissues as an epigenetic marker for cancer risk.MethodsA systematic literature search in the Medline database, using PubMed, was conducted for epidemiological studies, published before March 2014. The random-effects model was used to estimate weighted mean differences (MDs) with 95% Confidence Intervals (CIs). Furthermore, subgroup analyses were conducted by sample type (tissue or blood samples), cancer types, and by assays used to measure global DNA methylation levels. The Cochrane software package Review Manager 5.2 was used.ResultsA total of 19 unique articles on 6107 samples (2554 from cancer patients and 3553 control samples) were included in the meta-analysis. LINE-1 methylation levels were significantly lower in cancer patients than in controls (MD: −6.40, 95% CI: −7.71, −5.09; p<0.001). The significant difference in methylation levels was confirmed in tissue samples (MD −7.55; 95% CI: −9.14, −65.95; p<0.001), but not in blood samples (MD: −0.26, 95% CI: −0.69, 0.17; p = 0.23). LINE-1 methylation levels were significantly lower in colorectal and gastric cancer patients than in controls (MD: −8.33; 95% CI: −10.56, −6.10; p<0.001 and MD: −5.75; 95% CI: −7.75, −3.74; p<0.001) whereas, no significant difference was observed for hepatocellular cancer.ConclusionsThe present meta-analysis adds new evidence to the growing literature on the role of LINE-1 hypomethylation in human cancer and demonstrates that LINE-1 methylation levels were significantly lower in cancer patients than in control samples, especially in certain cancer types. This result was confirmed in tissue samples, both fresh/frozen or FFPE specimens, but not in blood. Further studies are needed to better clarify the role of LINE-1 methylation in specific subgroups, considering both cancer and sample type, and the methods of measurement.

Maternal phthalate exposure during pregnancy is associated with DNA methylation of LINE-1 and Alu repetitive elements in Mexican-American children

“…Their high rates of methylation are likely responsible for the suppression of their transposition activity and thus lower levels of methylation of Alu and LINE-1 may lead to genomic instability (Xiao-Jie et al, 2015). Lower levels of methylation of LINE-1 and Alu elements has been associated with several cancers (Barchitta et al, 2014; Li et al, 2014; Salas et al, 2014) as well as some phthalate-related health outcomes such as obesity and sperm quality (Perng et al, 2013; Tian et al, 2014). However, it remains unclear how differences in DNA methylation of repetitive elements associated with prenatal phthalate exposures lead to health effects.…”

Endogenous retroviral promoter exaptation in human cancer

“…The most well established epigenetic changes are promoter hypermethylation and associated silencing of tumor suppressor genes [95, 99, 100] as well as genome-wide DNA hypomethylation [101–103]. Hypomethylation of ERVs and L1s in many tumors has been documented [104–106] and general transcriptional up-regulation of ERVs and L1s is often observed in cancers [33, 107–109]. However, other studies have shown no significant changes in ERV expression in selected human cancers compared to corresponding normal tissues [110, 111].…”

The Human Long Interspersed Element-1 Retrotransposon: An Emerging Biomarker of Neoplasia

“…A meta-analysis of LINE-1 hypomethylation as a marker for cancer risk revealed that tissue-based DNA assays fairly consistently reveal LINE-1 hypomethylation in cancers compared to controls (57). In contrast, LINE-1 methylation status in blood is apparently not a marker of cancer risk across 19 studies included in the meta-analysis, suggesting that direct assays of malignant tissues are more sensitive to these changes (57).…”

“…In contrast, LINE-1 methylation status in blood is apparently not a marker of cancer risk across 19 studies included in the meta-analysis, suggesting that direct assays of malignant tissues are more sensitive to these changes (57). …”