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Meta-Analysis
. 2014 Oct 2;9(10):e109478.
doi: 10.1371/journal.pone.0109478. eCollection 2014.

LINE-1 hypomethylation in blood and tissue samples as an epigenetic marker for cancer risk: a systematic review and meta-analysis

Martina Barchitta  1 , Annalisa Quattrocchi  1 , Andrea Maugeri  1 , Manlio Vinciguerra  2 , Antonella Agodi  1
Affiliations
Meta-Analysis

LINE-1 hypomethylation in blood and tissue samples as an epigenetic marker for cancer risk: a systematic review and meta-analysis

Martina Barchitta et al. PLoS One. .

Abstract

Objective: A 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.

Methods: A 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.

Results: A 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.

Conclusions: The 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.

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Conflict of interest statement

Competing Interests: Manlio Vinciguerra has served as a PLOS ONE Editorial Board member for three years. This does not alter the authors' adherence to PLOS ONE Editorial policies and criteria.

Figures

Figure 1
Figure 1. Flow diagram of study selection.
Figure 2
Figure 2. Forest plot of the mean difference of LINE-1 methylation levels between cancer and control groups in tissue and blood samples.
Subgroup analysis based on sample type.
Figure 3
Figure 3. Forest plot of the mean difference of LINE-1 methylation levels between cancer and control groups in tissue samples.
Subgroups analysis based on sample source.
Figure 4
Figure 4. Forest plot of the mean difference of LINE-1 methylation levels between cancer and control groups.
Subgroups analysis based on cancer type.
Figure 5
Figure 5. Forest plot of the mean difference of LINE-1 methylation levels between cancer and control groups.
Subgroups analysis based on method.
Figure 6
Figure 6. Forest plot of the mean difference of LINE-1 methylation levels between cancer and control groups in tissue samples.
Subgroups analysis based on method.
Figure 7
Figure 7. Funnel plot.
Subgroup analysis based on sample type.
Figure 8
Figure 8. Funnel plot.
Subgroup analysis based on tissue specimen types. SE, standard error, MD, mean difference.
Figure 9
Figure 9. Funnel plot.
Subgroup analysis based on cancer type in blood samples.
Figure 10
Figure 10. Funnel plot.
Subgroup analysis based on cancer type in tissue samples.
Figure 11
Figure 11. Funnel plot.
Subgroup analysis based on detection method in blood samples.
Figure 12
Figure 12. Funnel plot.
Subgroup analysis based on detection method in tissue samples.
See this image and copyright information in PMC

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