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Total DNA Methylation Changes Reflect Random Oxidative DNA Damage in Gliomas.

ABSTRACT: DNA modifications can be used to monitor pathological processes. We have previously shown that estimating the amount of the main DNA epigenetic mark, 5-methylcytosine (m⁵C), is an efficient and reliable way to diagnose brain tumors, hypertension, and other diseases. Abnormal increases of reactive oxygen species (ROS) are a driving factor for mutations that lead to changes in m⁵C levels and cancer evolution. 8-oxo-deoxyguanosine (8-oxo-dG) is a specific marker of ROS-driven DNA-damage, and its accumulation makes m⁵C a hotspot for mutations. It is unknown how m⁵C and 8-oxo-dG correlate with the malignancy of gliomas. We analyzed the total contents of m⁵C and 8-oxo-dG in DNA from tumor tissue and peripheral blood samples from brain glioma patients. We found an opposite relationship in the amounts of m⁵C and 8-oxo-dG, which correlated with glioma grade in the way that low level of m⁵C and high level of 8-oxo-dG indicated increased glioma malignancy grade. Our results could be directly applied to patient monitoring and treatment protocols for gliomas, as well as bolster previous findings, suggesting that spontaneously generated ROS react with m⁵C. Because of the similar mechanisms of m⁵C and guanosine oxidation, we concluded that 8-oxo-dG could also predict glioma malignancy grade and global DNA demethylation in cancer cells.

SUBMITTER: Barciszewska AM

PROVIDER: S-EPMC6770701 | biostudies-literature | 2019 Sep

REPOSITORIES: biostudies-literature

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Total DNA Methylation Changes Reflect Random Oxidative DNA Damage in Gliomas.

Barciszewska Anna-Maria AM Giel-Pietraszuk Małgorzata M Perrigue Patrick M PM Naskręt-Barciszewska Mirosława M

Cells 20190911 9

DNA modifications can be used to monitor pathological processes. We have previously shown that estimating the amount of the main DNA epigenetic mark, 5-methylcytosine (m<sup>5</sup>C), is an efficient and reliable way to diagnose brain tumors, hypertension, and other diseases. Abnormal increases of reactive oxygen species (ROS) are a driving factor for mutations that lead to changes in m<sup>5</sup>C levels and cancer evolution. 8-oxo-deoxyguanosine (8-oxo-dG) is a specific marker of ROS-driven ...[more]

PMID: 31514401

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Project description:BackgroundMeningiomas are the most common primary intracranial tumors in adults. They are initially detected with neuroimaging techniques, but definite histological diagnosis requires tumor surgery to collect tumor tissue. Gross total resection is an optimal and final treatment for the majority of patients, followed by radiotherapy in malignant or refractory cases. However, there are a lot of uncertainties about i.a. the need for intervention in incidental cases, estimation of growth kinetics, risk of malignant transformation, or response to radiotherapy. Therefore a new diagnostic approach is needed. It has already been shown that epigenetics plays a crucial role in cancer biology, development, and progression. DNA methylation, the presence of 5-methylcytosine in DNA, is one of the main elements of a broad epigenetic program in a eukaryotic cell, with superior regulatory significance. Therefore, we decided to look at meningioma through changes of 5-methylcytosine.MethodsWe performed an analysis of the total amount of 5-methylcytosine in DNA isolated from intracranial meningioma tissues and peripheral blood samples of the same patients. The separation and identification of radioactively labeled nucleotides were performed using thin-layer chromatography.ResultsWe found that the 5-methylcytosine level in DNA from intracranial meningiomas is inversely proportional to the malignancy grade. The higher the tumor WHO grade is, the lower the total DNA methylation. The amount of 5-methylcytosine in tumor tissue and peripheral blood is almost identical.ConclusionsWe conclude that the total DNA methylation can be a useful marker for brain meningioma detection, differentiation, and monitoring. It correlates with tumor WHO grade, and the 5-methylcytosine level in peripheral blood reflects that in tumor tissue. Therefore it's applicable for liquid biopsy. Our study creates a scope for further research on epigenetic mechanisms in neurooncology and can lead to the development of new diagnostic methods in clinical practice.

Project description:BACKGROUND:Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a lifelong debilitating disease with a complex pathology not yet clearly defined. Susceptibility to ME/CFS involves genetic predisposition and exposure to environmental factors, suggesting an epigenetic association. Epigenetic studies with other ME/CFS cohorts have used array-based technology to identify differentially methylated individual sites. Changes in RNA quantities and protein abundance have been documented in our previous investigations with the same ME/CFS cohort used for this study. RESULTS:DNA from a well-characterised New Zealand cohort of 10 ME/CFS patients and 10 age-/sex-matched healthy controls was isolated from peripheral blood mononuclear (PBMC) cells, and used to generate reduced genome-scale DNA methylation maps using reduced representation bisulphite sequencing (RRBS). The sequencing data were analysed utilising the DMAP analysis pipeline to identify differentially methylated fragments, and the MethylKit pipeline was used to quantify methylation differences at individual CpG sites. DMAP identified 76 differentially methylated fragments and Methylkit identified 394 differentially methylated cytosines that included both hyper- and hypo-methylation. Four clusters were identified where differentially methylated DNA fragments overlapped with or were within close proximity to multiple differentially methylated individual cytosines. These clusters identified regulatory regions for 17 protein encoding genes related to metabolic and immune activity. Analysis of differentially methylated gene bodies (exons/introns) identified 122 unique genes. Comparison with other studies on PBMCs from ME/CFS patients and controls with array technology showed 59% of the genes identified in this study were also found in one or more of these studies. Functional pathway enrichment analysis identified 30 associated pathways. These included immune, metabolic and neurological-related functions differentially regulated in ME/CFS patients compared to the matched healthy controls. CONCLUSIONS:Major differences were identified in the DNA methylation patterns of ME/CFS patients that clearly distinguished them from the healthy controls. Over half found in gene bodies with RRBS in this study had been identified in other ME/CFS studies using the same cells but with array technology. Within the enriched functional immune, metabolic and neurological pathways, a number of enriched neurotransmitter and neuropeptide reactome pathways highlighted a disturbed neurological pathophysiology within the patient group.

Project description:ObjectiveObesity is driven by modifiable lifestyle factors whose effects may be mediated by epigenetics. Therefore, we investigated lifestyle effects on blood DNA methylation in participants of the LIFE-Adult study, a well-characterised population-based cohort from Germany.Research design and methodsLifestyle scores (LS) based on diet, physical activity, smoking and alcohol intake were calculated in 4107 participants of the LIFE-Adult study. Fifty subjects with an extremely healthy lifestyle and 50 with an extremely unhealthy lifestyle (5th and 95th percentiles LS) were selected for genome-wide DNA methylation analysis in blood samples employing Illumina Infinium® Methylation EPIC BeadChip system technology.ResultsDifferences in DNA methylation patterns between body mass index groups (<25 vs. >30 kg/m2 ) were rather marginal compared to inter-lifestyle differences (0 vs. 145 differentially methylated positions [DMPs]), which identified 4682 differentially methylated regions (DMRs; false discovery rate [FDR <5%) annotated to 4426 unique genes. A DMR annotated to the glutamine-fructose-6-phosphate transaminase 2 (GFPT2) locus showed the strongest hypomethylation (∼6.9%), and one annotated to glutamate rich 1 (ERICH1) showed the strongest hypermethylation (∼5.4%) in healthy compared to unhealthy lifestyle individuals. Intersection analysis showed that diet, physical activity, smoking and alcohol intake equally contributed to the observed differences, which affected, among others, pathways related to glutamatergic synapses (adj. p < .01) and axon guidance (adj. p < .05). We showed that methylation age correlates with chronological age and waist-to-hip ratio with lower DNA methylation age (DNAmAge) acceleration distances in participants with healthy lifestyles. Finally, two identified top DMPs for the alanyl aminopeptidase (ANPEP) locus also showed the strongest expression quantitative trait methylation in blood.ConclusionsDNA methylation patterns help discriminate individuals with a healthy versus unhealthy lifestyle, which may mask subtle methylation differences derived from obesity.

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Total DNA Methylation Changes Reflect Random Oxidative DNA Damage in Gliomas.

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Total DNA Methylation Changes Reflect Random Oxidative DNA Damage in Gliomas.

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