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Translational Psychiatry Feb 2019There has been a limited number of systematic reviews conducted to summarize the overview of the relationship between DNA methylation and depression, and to critically...
There has been a limited number of systematic reviews conducted to summarize the overview of the relationship between DNA methylation and depression, and to critically appraise the roles of major study characteristics in the accuracy of study findings. This systematic review aims to critically appraise the impact of study characteristics on the association between DNA methylation and depression, and summarize the overview of this association. Electronic databases and gray literatures until December 2017 were searched for English-language studies with standard diagnostic criteria of depression. A total of 67 studies were included in this review along with a summary of their study characteristics. We grouped the findings into etiological and treatment studies. Majority of these selected studies were recently published and from developed countries. Whole blood samples were the most studied common tissues. Bisulfite conversion, along with pyrosequencing, was widely used to test the DNA methylation level across all the studies. High heterogeneity existed among the studies in terms of experimental and statistical methodologies and study designs. As recommended by the Cochrane guideline, a systematic review without meta-analysis should be undertaken. This review has, in general, found that DNA methylation modifications were associated with depression. Subgroup analyses showed that most studies found BDNF and SLC6A4 hypermethylations to be associated with MDD or depression in general. In contrast, studies on NR3C1, OXTR, and other genes, which were tested by only few studies, reported mixed findings. More longitudinal studies using standardized experimental and laboratory methodologies are needed in future studies to enable more systematical comparisons and quantitative synthesis.
Topics: DNA Methylation; Depression; Depressive Disorder; Humans
PubMed: 30718449
DOI: 10.1038/s41398-019-0412-y -
Archives of Medical Research May 2013We undertook this study to comprehensively summarize the associations between MGMT promoter methylation and prognosis of glioblastoma (GBM). (Meta-Analysis)
Meta-Analysis Review
BACKGROUND AND AIMS
We undertook this study to comprehensively summarize the associations between MGMT promoter methylation and prognosis of glioblastoma (GBM).
METHODS
We searched PubMed, EMBASE and Cochrane databases (from January 2003 to November 1, 2011) and the references of the relevant articles in English with hazard ratios (HRs) and 95% confidence intervals (95% CIs). Two reviewers independently extracted data using a standardized form. Discrepancies were adjudicated by discussion.
RESULTS
Twenty four studies met the inclusion criteria. There were 22 studies reporting on the relationship between MGMT methylation and overall survival (OS) of GBM and 12 studies on the association between MGMT methylation and progression-free survival (PFS) of GBM. Patients with a methylated status of MGMT had significant OS and PFS advantage (HR = 0.48, 95% CI: 0.35-0.65; I² = 79.78 for OS; HR = 0.43, 95% CI: 0.32-0.56; I² = 50.38 for PFS). Pooled HRs remained significant in further subgroup analysis based on the year of publication and continents of studies.
CONCLUSIONS
Patients with MGMT promoter methylation had significant OS and PFS advantage than those without methylated status.
Topics: Brain Neoplasms; DNA Methylation; Disease-Free Survival; Genetic Heterogeneity; Glioblastoma; Humans; Methylation; O(6)-Methylguanine-DNA Methyltransferase; Prognosis; Promoter Regions, Genetic
PubMed: 23608672
DOI: 10.1016/j.arcmed.2013.04.004 -
Clinical Epigenetics Aug 2020DNA methylation biomarkers in stool may have applications in early colorectal cancer (CRC) detection; however, their association with stages of CRC carcinogenesis or...
BACKGROUND
DNA methylation biomarkers in stool may have applications in early colorectal cancer (CRC) detection; however, their association with stages of CRC carcinogenesis or their performance in detecting various stages is unclear. We aimed to systematically review the evidence for DNA methylation markers in stool for risk stratification or detection of specific CRC stages, as well as precursors of CRC.
METHODS
We conducted a systematic search in line with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. We searched PubMed and ISI Web of Knowledge to identify relevant studies published until 14th January 2020. Two reviewers independently extracted data on study population characteristics, candidate genes, methylation measurement methods, odds ratios (ORs), overall and stage-specific sensitivities, specificities, areas under the receiver operating characteristics curve, and p-values for statistical significance for OR and for association of methylation levels with stage.
RESULTS
Twenty-seven studies that reported stage-specific associations or performances of fecal DNA methylation markers for detecting colorectal neoplasms were identified. All studies used methylation-specific polymerase chain reaction for assessing methylation levels in the promoter or exon 1 regions of targeted genes. However, most studies were underpowered and limited by their case-control design. Furthermore, the stage-specific associations or sensitivities were validated for two markers (hypermethylation of GATA4 and VIM) only.
CONCLUSION
Methylation markers in stool may be useful for detection of CRC precursors or CRC staging, but promising candidate markers need to be validated in longitudinal studies on large screening populations, performing epigenome-wide analyses. Identification of stage-specific DNA methylation biomarkers in stool could boost current strategies towards early detection and enable different approaches to precision medicine for CRC.
Topics: Biomarkers, Tumor; Colorectal Neoplasms; DNA Methylation; Epigenesis, Genetic; Feces; Genetic Markers; Humans; Neoplasm Staging
PubMed: 32778176
DOI: 10.1186/s13148-020-00904-7 -
Artificial Intelligence in Medicine Sep 2023DNA methylation biomarkers have great potential in improving prognostic classification systems for patients with cancer. Machine learning (ML)-based analytic techniques... (Review)
Review
BACKGROUND
DNA methylation biomarkers have great potential in improving prognostic classification systems for patients with cancer. Machine learning (ML)-based analytic techniques might help overcome the challenges of analyzing high-dimensional data in relatively small sample sizes. This systematic review summarizes the current use of ML-based methods in epigenome-wide studies for the identification of DNA methylation signatures associated with cancer prognosis.
METHODS
We searched three electronic databases including PubMed, EMBASE, and Web of Science for articles published until 2 January 2023. ML-based methods and workflows used to identify DNA methylation signatures associated with cancer prognosis were extracted and summarized. Two authors independently assessed the methodological quality of included studies by a seven-item checklist adapted from 'A Tool to Assess Risk of Bias and Applicability of Prediction Model Studies (PROBAST)' and from the 'Reporting Recommendations for Tumor Marker Prognostic Studies (REMARK). Different ML methods and workflows used in included studies were summarized and visualized by a sunburst chart, a bubble chart, and Sankey diagrams, respectively.
RESULTS
Eighty-three studies were included in this review. Three major types of ML-based workflows were identified. 1) unsupervised clustering, 2) supervised feature selection, and 3) deep learning-based feature transformation. For the three workflows, the most frequently used ML techniques were consensus clustering, least absolute shrinkage and selection operator (LASSO), and autoencoder, respectively. The systematic review revealed that the performance of these approaches has not been adequately evaluated yet and that methodological and reporting flaws were common in the identified studies using ML techniques.
CONCLUSIONS
There is great heterogeneity in ML-based methodological strategies used by epigenome-wide studies to identify DNA methylation markers associated with cancer prognosis. In theory, most existing workflows could not handle the high multi-collinearity and potentially non-linearity interactions in epigenome-wide DNA methylation data. Benchmarking studies are needed to compare the relative performance of various approaches for specific cancer types. Adherence to relevant methodological and reporting guidelines are urgently needed.
Topics: Humans; DNA Methylation; Epigenome; Prognosis; Neoplasms; Machine Learning
PubMed: 37673571
DOI: 10.1016/j.artmed.2023.102589 -
Journal of Autoimmunity Mar 2017Psoriasis is an inflammatory disease of the skin that is sometimes accompanied by an auto-inflammatory arthritis called psoriatic arthritis (PsA). Psoriasis and PsA are... (Meta-Analysis)
Meta-Analysis Review
Psoriasis is an inflammatory disease of the skin that is sometimes accompanied by an auto-inflammatory arthritis called psoriatic arthritis (PsA). Psoriasis and PsA are multifactorial diseases that result from complex interactions of environmental and genetic risk factors. Epigenetic marks, which are labile chemical marks with diverse functions, form a layer of biological information that sits at the interface of genetics and the environment. Aberrant epigenetic regulation has been previously implicated in other rheumatological disorders. The purpose of this review is to summarize and critically evaluate the nascent literature on epigenetics in psoriasis and PsA. A systematic review yielded 52 primary articles after applying inclusion and exclusion criteria. Data were extracted using a standardized template and study quality assessed using a methodological quality checklist. Studies reflect a broad range of epigenetic sub-disciplines, the most common being DNA methylation, followed by the parent of origin effect or genomic imprinting, expression or activity of epigenetic modifying enzymes, and histone modifications. Epidemiological studies demonstrating excessive paternal transmission provided the earliest evidence of epigenetic deregulation in psoriatic disease, however few studies have examined its molecular mechanisms. Methylation studies evolved rapidly from low resolution global to targeted analyses of known psoriatic disease susceptibility loci such as HLA-C*0602. The recent explosion of epigenome-wide association studies has provided us with novel insights into psoriasis pathogenesis, and the mechanism of action of UVB, methotrexate, and anti-TNF therapies, as well as molecular signatures of psoriasis that may have clinical relevance. Finally, recent studies of pharmacological inhibitors of epigenetic modifier enzymes demonstrate their potential applicability as novel treatment modalities for psoriasis. Challenges of epigenetics research in psoriasis and PsA were identified and future perspectives are discussed herein.
Topics: Arthritis, Psoriatic; DNA Methylation; Epigenesis, Genetic; Epigenomics; Genetic Association Studies; Genetic Predisposition to Disease; Genomic Imprinting; Histones; Humans; Organ Specificity; Psoriasis
PubMed: 27965059
DOI: 10.1016/j.jaut.2016.12.002 -
Current Oncology (Toronto, Ont.) Feb 2023Outcomes for patients with high-grade glioma remain poor. Temozolomide (TMZ) is the only drug approved for first-line treatment of glioblastoma multiforme, the most... (Review)
Review
Outcomes for patients with high-grade glioma remain poor. Temozolomide (TMZ) is the only drug approved for first-line treatment of glioblastoma multiforme, the most aggressive form of glioma. Chronotherapy highlights the potential benefit of timed TMZ administration. This is based on pre-clinical studies of enhanced TMZ-induced glioma cytotoxicity dependent on circadian, oscillating expression of key genes involved in apoptosis, DNA damage repair, and cell-cycle mediated cell death. The current systematic review's primary aim was to evaluate the efficacy and toxicity of TMZ chronotherapy. A systemic review of literature following PRISMA guidelines looking at clinical outcomes on TMZ chronotherapy on gliomas was performed. The search in the English language included three databases (PubMed, EMBASE, and Cochrane) and five conferences from 1946 to April 2022. Two independent reviewers undertook screening, data extraction, and risk-of-bias assessment. A descriptive analysis was conducted due to limited data. Of the 269 articles screened, two unique studies were eligible and underwent abstraction for survival and toxicity findings. Both studies-one a retrospective cohort study (n = 166) and the other a prospective randomized feasibility study (n = 35)-were conducted by the same academic group and suggested a trend for improved overall survival, but possibly increased toxicity when TMZ was administered in the morning (vs. evening). There was limited evidence suggesting possible therapeutic value from administering TMZ in the morning, which may be consistent with the pre-clinical observations of the importance of the timing of TMZ administration in vitro. Larger, pragmatic, prospective randomized controlled trials are needed to ascertain the value of TMZ chronotherapy to provide optimized and equitable care for this population.
Topics: Humans; Temozolomide; Retrospective Studies; Prospective Studies; Brain Neoplasms; Glioma; Chronotherapy; Randomized Controlled Trials as Topic
PubMed: 36826108
DOI: 10.3390/curroncol30020147 -
Schizophrenia Research Aug 2022Evidence suggests that schizophrenia (SZ) is associated with accelerated biological aging. DNA methylation can be used as an indicator of biological aging by means of... (Meta-Analysis)
Meta-Analysis
INTRODUCTION
Evidence suggests that schizophrenia (SZ) is associated with accelerated biological aging. DNA methylation can be used as an indicator of biological aging by means of epigenetic clock estimates.
OBJECTIVE
The aim of this systematic review and meta-analysis was to investigate the association between SZ and different epigenetic clocks.
METHODS
Search terms were applied in different databases: Embase, MEDLINE (EBSCO), Cochrane Central Register of Controlled Trials, PubMed, PsychINFO and Web of Science. To assess for risk of bias we utilized an adapted version of the Newcastle-Ottawa Scale. Meta-analyses were conducted using the random effects model and meta-regressions were used to assess factors associated with heterogeneity.
RESULTS
Eight studies were included (Controls, n = 3394; SZ subjects, n = 3096), which analyzed five different epigenetic clocks. Overall meta-analysis revealed no significant differences between SZ and controls on epigenetic aging (Standardized Mean Difference - SMD = -0.21; p = 0.13). However, epigenetic clock method was a significant moderator of heterogeneity (p = 0.004). Using Horvath's clock as reference, higher SMD's were found for PhenoAge and Intrinsic epigenetic age acceleration (IEAA) clocks. In a stratified meta-analysis restricted to the two clocks mentioned above, a significant accelerating effect was found in patients with SZ when compared to controls (SMD = 0.29; p = 0.003).
CONCLUSION
Our findings suggest that the method of epigenetic clocks is a critical factor associated with estimates of aging acceleration in SZ. However, more studies are needed to confirm these findings and in order to evaluate a possible minor effect in overall analysis.
Topics: Aging; DNA Methylation; Epigenesis, Genetic; Epigenomics; Humans; Schizophrenia
PubMed: 35780750
DOI: 10.1016/j.schres.2022.06.029 -
PloS One 2016Methylation of tumor suppressor gene promoter leads to transcription inactivation and is involved in tumorigenesis. Several studies demonstrate a potential association... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Methylation of tumor suppressor gene promoter leads to transcription inactivation and is involved in tumorigenesis. Several studies demonstrate a potential association between the Death-Associated Protein Kinase (DAPK) gene promoter methylation and bladder cancer risk, tumor stage and histological grade. Due to inconsistent results of these studies, we performed this meta-analysis to ascertain the association.
METHODS
Studies were retrieved from the PubMed, Embase, Web of Science and the Cochrane Library databases. Study selection and data extraction were executed by two reviewers independently. Meta-analysis was performed using Stata 13.0 and Review Manager 5.3 software.
RESULTS
A total of 21 articles involving 15 case control and 8 case series studies were included in this meta-analysis. DAPK promoter methylation was associated with bladder cancer risk (OR: 5.81; 95%CI = 3.83-8.82, P<0.00001). The frequency of DAPK promoter methylation was equal in bladder cancer tissue and paired adjacent normal tissue (OR: 0.87; 95%CI = 0.31-2.48, P = 0.794). Furthermore, DAPK promoter methylation was associated with higher histological grade (OR: 1.52; 95%CI = 1.10-2.09, P = 0.011) but not associated with tumor stage (OR: 1.12; 95%CI = 0.67-1.87, P = 0.668).
CONCLUSIONS
The result suggests that DAPK promoter methylation is significantly increased in bladder cancer patients compared to normal controls. DAPK promoter methylation could serve as a biomarker for bladder cancer detection and management.
Topics: Biomarkers, Tumor; Case-Control Studies; DNA Methylation; Death-Associated Protein Kinases; Genetic Association Studies; Genetic Predisposition to Disease; Humans; Neoplasm Grading; Neoplasm Staging; Odds Ratio; Promoter Regions, Genetic; Publication Bias; Risk; Urinary Bladder Neoplasms
PubMed: 27907054
DOI: 10.1371/journal.pone.0167228 -
Human Reproduction Update Nov 2020Studies in non-human mammals suggest that environmental factors can influence spermatozoal DNA methylation, and some research suggests that spermatozoal DNA methylation...
BACKGROUND
Studies in non-human mammals suggest that environmental factors can influence spermatozoal DNA methylation, and some research suggests that spermatozoal DNA methylation is also implicated in conditions such as subfertility and imprinting disorders in the offspring. Together with an increased availability of cost-effective methods of interrogating DNA methylation, this premise has led to an increasing number of studies investigating the DNA methylation landscape of human spermatozoa. However, how the human spermatozoal DNA methylome is influenced by environmental factors is still unclear, as is the role of human spermatozoal DNA methylation in subfertility and in influencing offspring health.
OBJECTIVE AND RATIONALE
The aim of this systematic review was to critically appraise the quality of the current body of literature on DNA methylation in human spermatozoa, summarize current knowledge and generate recommendations for future research.
SEARCH METHODS
A comprehensive literature search of the PubMed, Web of Science and Cochrane Library databases was conducted using the search terms 'semen' OR 'sperm' AND 'DNA methylation'. Publications from 1 January 2003 to 2 March 2020 that studied human sperm and were written in English were included. Studies that used sperm DNA methylation to develop methodologies or forensically identify semen were excluded, as were reviews, commentaries, meta-analyses or editorial texts. The Grading of Recommendations, Assessment, Development and Evaluations (GRADE) criteria were used to objectively evaluate quality of evidence in each included publication.
OUTCOMES
The search identified 446 records, of which 135 were included in the systematic review. These 135 studies were divided into three groups according to area of research; 56 studies investigated the influence of spermatozoal DNA methylation on male fertility and abnormal semen parameters, 20 studies investigated spermatozoal DNA methylation in pregnancy outcomes including offspring health and 59 studies assessed the influence of environmental factors on spermatozoal DNA methylation. Findings from studies that scored as 'high' and 'moderate' quality of evidence according to GRADE criteria were summarized. We found that male subfertility and abnormal semen parameters, in particular oligozoospermia, appear to be associated with abnormal spermatozoal DNA methylation of imprinted regions. However, no specific DNA methylation signature of either subfertility or abnormal semen parameters has been convincingly replicated in genome-scale, unbiased analyses. Furthermore, although findings require independent replication, current evidence suggests that the spermatozoal DNA methylome is influenced by cigarette smoking, advanced age and environmental pollutants. Importantly however, from a clinical point of view, there is no convincing evidence that changes in spermatozoal DNA methylation influence pregnancy outcomes or offspring health.
WIDER IMPLICATIONS
Although it appears that the human sperm DNA methylome can be influenced by certain environmental and physiological traits, no findings have been robustly replicated between studies. We have generated a set of recommendations that would enhance the reliability and robustness of findings of future analyses of the human sperm methylome. Such studies will likely require multicentre collaborations to reach appropriate sample sizes, and should incorporate phenotype data in more complex statistical models.
Topics: DNA Methylation; Female; Humans; Infertility, Male; Male; Pregnancy; Pregnancy Outcome; Reproducibility of Results; Semen; Spermatozoa
PubMed: 32790874
DOI: 10.1093/humupd/dmaa025 -
Environmental Science & Technology Oct 2023Polycyclic aromatic hydrocarbon (PAH) derivatives constitute a significant class of emerging contaminants that have been ubiquitously detected in diverse environmental... (Review)
Review
Polycyclic aromatic hydrocarbon (PAH) derivatives constitute a significant class of emerging contaminants that have been ubiquitously detected in diverse environmental matrixes, with some even exhibiting higher toxicities than their corresponding parent PAHs. To date, compared with parent PAHs, fewer systematic summaries and reanalyses are available for PAH derivatives with great environmental concerns. This review summarizes the current knowledge on the chemical species, levels, biotransformation patterns, chemical analytical methods, internal exposure routes with representative biomarkers, and toxicity of PAH derivatives, primarily focusing on nitrated PAHs (NPAHs), oxygenated PAHs (OPAHs), halogenated PAHs (XPAHs), and alkylated PAHs (APAHs). A collection of 188 compounds from four categories, 44 NPAHs, 36 OPAHs, 56 APAHs, and 52 XPAHs, has been compiled from 114 studies that documented the environmental presence of PAH derivatives. These compounds exhibited weighted average air concentrations that varied from a lower limit of 0.019 pg/m to a higher threshold of 4060 pg/m. Different analytical methods utilizing comprehensive two-dimensional gas chromatography coupled with high-resolution time-of-flight mass spectrometry (GC × GC-TOF-MS), gas chromatography coupled to time-of-flight mass spectrometry (GC-TOF-MS), comprehensive two-dimensional gas chromatography coupled to quadrupole mass spectrometry (GC × GC-QQQ-MS), and Fourier-transform ion cyclotron resonance mass spectrometry (FT-ICR MS), that adopted untargeted strategies for the identification of PAH derivatives are also reviewed here. Additionally, an in-depth analysis of biotransformation patterns for each category is provided, including the likelihood of specific biotransformation reaction types. For the toxicity, we primarily summarized key metabolic activation pathways, which could result in the formation of reactive metabolites capable of covalently bonding with DNA and tissue proteins, and potential health outcomes such as carcinogenicity and genotoxicity, oxidative stress, inflammation and immunotoxicity, and developmental toxicity that might be mediated by the aryl hydrocarbon receptor (AhR). Finally, we pinpoint research challenges and emphasize the need for further studies on identifying PAH derivatives, tracking external exposure levels, evaluating internal exposure levels and associated toxicity, clarifying exposure routes, and considering mixture exposure effects. This review aims to provide a broad understanding of PAH derivatives' identification, environmental occurrence, human exposure, biotransformation, and toxicity, offering a valuable reference for guiding future research in this underexplored area.
PubMed: 37703436
DOI: 10.1021/acs.est.3c03170