Aberrant Methylation of LINE-1 Transposable Elements: A Search for Cancer Biomarkers
Abstract
:1. Introduction
2. LINE-1 Retrotransposons in the Human Genome
2.1. L1 Methylation in Cancer Diagnostics
2.2. L1 Methylation in Cancer Prognosis
3. Circulating DNA as a Source of Cancer Biomarkers
3.1. Methylation of Circulating L1 in the Healthy State
3.2. Perspectives of Using Aberrantly Methylated Circulating L1 for Cancer Diagnostics and Prognosis
4. Final Remarks
Funding
Conflicts of Interest
References
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Cancer Type | Methods | Diagnostic Value (*) | Prognostic Value | Ref. |
---|---|---|---|---|
Breast cancer | Pyrosequencing | Normal tissues—92%, IBC tissues—86% | L1 hypomethylation was significantly associated with decreased OS (HR 2.19, 95% CI 1.17–4.09), decreased DFS (HR 2.05, 95% CI 1.14–3.67), and increased DR (HR 2.83, 95 % CI 1.53–5.21) in younger (≤55 years) but not in older patients (>55 years) | [54] |
Pyrosequencing | Normal tissues—64%, IBC tissues—61% | - | [55] | |
Hepatocellular carcinoma | Bisulfite-specific PCR and DNA sequencing analysis | Normal tissues—60%, tumor tissues—34% | Patients with L1 hypomethylation had decreased median postresection TFS (22 months [95% CI: 13.3–30.7]) and OS (35 months [95% CI: 24.0–46.1]) compared to those with L1 hypermethylation (40 and 60 months, respectively) | [56] |
Pyrosequencing | Normal tissues—68%, tumor tissues—48% | - | [57] | |
Normal tissues—57%, tumor tissues—46% | - | [58] | ||
Esophageal cell carcinoma | Pyrosequencing | Normal tissues—82%, tumor tissues—64% | - | [59] |
Normal tissues—79%, tumor tissues—63% | L1 methylation was significantly associated with DFS (univariate HR 2.32, 95% CI 1.38–3.84, methylation level [quartile] < 56%; multivariate HR 1.81, 95% CI 1.06–3.05) and CSS (univariate HR 2.21, 95% CI 1.33–3.60; multivariate HR 1.87, 95% CI 1.12–3.08) | [60] | ||
Quantitative real-time MSP | Normal tissues—90%, tumor tissues—78% | Cumulative survival was significantly shorter for ESCC patients with L1 methylation level ≤ 78% than for those with > 78% (34 vs. 43 months) | [61] | |
Colorectal cancer | Pyrosequencing | Normal tissues—77%, tumor tissues—57% | OS was significantly longer in patients with L1 methylation level ≥ 65% | [62] |
MSP-PCR, pyrosequencing after assay validation | - | L1 hypomethylation was significantly associated with higher CRC-specific mortality (for 10% decrease in L1 methylation: HR 2.45, 95% CI 1.64–3.66) | [63] | |
MethyLight assay | - | PFS, OS, and 5-year OPS were significantly shorter in patients with low L1 methylation than in those with high L1 methylation (HR 1.00 vs. HR 2.74 [95% CI 1.19–6.29]) | [64] | |
Quantitative PCR | - | L1 hypomethylation was significantly associated with lower OS (HR 1.68, 95% CI 1.03–2.75); the association was stronger in patients > 65 years (HR 2.00, 95% CI 1.13–3.52) | [65] | |
Gastric and colon cancers | Pyrosequencing | Colon: normal tissues—67%, tumor tissues—61% Gastric: normal tissues—66%, tumor tissues—62% | - | [66] |
Gastric cancer | Pyrosequencing | Chronic gastritis—62%, cancer—52% | L1 hypomethylation level (<51%) was significantly associated with shorter DFS and OS | [67] |
Lung cancer | Pyrosequencing | Normal tissues—74%, ADC tissues—67% | Patients with low L1 methylation levels (19–69%) had significantly higher recurrence rates and shorter DFS compared to those with high methylation levels (74–81%) | [68] |
- | L1 hypomethylation (<52%) was significantly associated with lower survival rates in patients with ADC stage I | [69] | ||
Bisulfite-PCR, pyrosequencing | Normal tissues—70%, ADC tissues—63%, SCC tissues—38% | L1 hypomethylation (≤58%) was independently associated with poor prognosis (p = 0.025) | [70] | |
Oropharyngeal squamous cell carcinoma | Quantitative MSP-PCR | - | L1 hypomethylation (<50% vs. ≥70%) was significantly associated with higher risk of early disease relapse (OR = 3.51; 95% CI 1.03–12.00) | [71] |
Tumor Location | Clinical Samples | Method | Results | Ref. |
---|---|---|---|---|
Colorectal (patients before treatment) | Plasma | AQAMA qPCR | Significant decrease of L1 MI in cancer patients compared with healthy subjects Association of L1MI with disease progression (advanced stage and distant metastasis) | [112] |
Lung (patients before treatment) | Cell surface-bound fraction of blood | MIRA | Significant decrease of L1 MI in cancer patients compared with healthy subjects Hypomethylation of L1 promoters in cancer patients is more pronounced for the L1 human-specific (L1Hs) family | [115] |
Lung (patients before treatment and after antitumor therapy) | Cell surface-bound fraction of blood | qMSP PCR | Association of L1 MI with tumor histological type Dynamic changes in L1 MI of csb-cirDNA during the follow-up period | [117] |
Lung (patients before treatment) | Cell surface-bound fraction of blood, plasma | qMSP PCR | Significant decrease of L1 MI in csb-cirDNA in cancer patients compared with healthy subjects | [116] |
Lung (patients before treatment) | Cell surface-bound fraction of blood, plasma | qMSP PCR | Decrease of L1 MI in cancer patients compared with the joint control group (healthy subjects + patients with bronchitis + COPD patients) and with COPD patients | [118] |
Diffuse large B cell lymphoma (patients before treatment) | Plasma | Pyrosequencing | Association of L1 hypomethylation with poor overall survival | [119] |
Melanoma (patients before treatment) | Serum | AQAMA qPCR | Decrease of L1 methylation during disease progression (advanced stage) | [120] |
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Ponomaryova, A.A.; Rykova, E.Y.; Gervas, P.A.; Cherdyntseva, N.V.; Mamedov, I.Z.; Azhikina, T.L. Aberrant Methylation of LINE-1 Transposable Elements: A Search for Cancer Biomarkers. Cells 2020, 9, 2017. https://doi.org/10.3390/cells9092017
Ponomaryova AA, Rykova EY, Gervas PA, Cherdyntseva NV, Mamedov IZ, Azhikina TL. Aberrant Methylation of LINE-1 Transposable Elements: A Search for Cancer Biomarkers. Cells. 2020; 9(9):2017. https://doi.org/10.3390/cells9092017
Chicago/Turabian StylePonomaryova, Anastasia A., Elena Y. Rykova, Polina A. Gervas, Nadezhda V. Cherdyntseva, Ilgar Z. Mamedov, and Tatyana L. Azhikina. 2020. "Aberrant Methylation of LINE-1 Transposable Elements: A Search for Cancer Biomarkers" Cells 9, no. 9: 2017. https://doi.org/10.3390/cells9092017