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Molecular Genetics & Genomic Medicine Sep 2018There are many studies with different results that examine the association between Catechol-O-MethylTransferase (COMT) gene single-nucleotide polymorphisms (SNPs) and... (Meta-Analysis)
Meta-Analysis
BACKGROUND
There are many studies with different results that examine the association between Catechol-O-MethylTransferase (COMT) gene single-nucleotide polymorphisms (SNPs) and schizophrenia. In this study, the aim was to conduct a meta-analysis to achieve a pooled effect size of the association between COMT gene rs165599 SNP and schizophrenia.
METHODS
Odds ratio (OR) was used as an effect size to determine the association between schizophrenia and the SNP. The pooled ORs were achieved under four different genetic models. When the heterogeneity among studies was high the DerSimonian-Laird random-effects model, otherwise the Mantel-Haenszel fixed-effects model was used. Publication bias was evaluated by Egger's test.
RESULTS
Under different genetic models no statistically significant association was found between rs165599 SNP and schizophrenia by meta-analyses consist of 20 independent studies. There was high heterogeneity among studies, for the possible reason the population differences, although the subgroup analyzes reduced the heterogeneity, no association was obtained. However, the sex-specific estimation of the females showed that to be a G allele carrier is a risk factor for schizophrenia (OR = 1.366 [95% confidence interval = 1.094-1.706]) compared to AA homozygous.
CONCLUSION
The COMT gene rs165599 SNP does not appear to be a single-risk factor for schizophrenia.
Topics: Case-Control Studies; Catechol O-Methyltransferase; Female; Humans; Male; Polymorphism, Single Nucleotide; Risk Factors; Schizophrenia
PubMed: 30165727
DOI: 10.1002/mgg3.468 -
Targeted Oncology Feb 2018Inhibition of DNA methyltransferases (DNMTs) has emerged as a novel treatment strategy in solid tumors. Aberrant hypermethylation in promoters of critical tumor...
Inhibition of DNA methyltransferases (DNMTs) has emerged as a novel treatment strategy in solid tumors. Aberrant hypermethylation in promoters of critical tumor suppressor genes is the basis for the idea that treatment with hypomethylating agents may lead to the restoration of a "normal" epigenome and produce clinically meaningful therapeutic outcomes. The aim of this review article is to summarize the current state of knowledge of DNMT inhibitors in the treatment of genitourinary malignancies. The efficacy of these agents in genitourinary malignancies was reported in a number of studies and suggests a role of induced DNA hypomethylation in overcoming resistance to conventional cytotoxic treatments. The clinical significance of these findings should be further investigated.
Topics: DNA Methylation; Humans; Urogenital Neoplasms
PubMed: 29230671
DOI: 10.1007/s11523-017-0546-x -
Neuro-oncology Sep 2021The DNA repair protein O6-methylguanine-DNA methyltransferase (MGMT) causes resistance of tumor cells to alkylating agents. It is a predictive biomarker in high-grade... (Meta-Analysis)
Meta-Analysis
MGMT promoter methylation testing to predict overall survival in people with glioblastoma treated with temozolomide: a comprehensive meta-analysis based on a Cochrane Systematic Review.
BACKGROUND
The DNA repair protein O6-methylguanine-DNA methyltransferase (MGMT) causes resistance of tumor cells to alkylating agents. It is a predictive biomarker in high-grade gliomas treated with temozolomide, however, there is no consensus on which test method, methylation sites, and cutoff values to use.
METHODS
We performed a Cochrane Review to examine studies using different techniques to measure MGMT and predict survival in glioblastoma patients treated with temozolomide. Eligible longitudinal studies included (i) adults with glioblastoma treated with temozolomide with or without radiotherapy, or surgery; (ii) where MGMT status was determined in tumor tissue, and assessed by 1 or more technique; and (iii) where overall survival was an outcome parameter, with sufficient information to estimate hazard ratios (HRs). Two or more methods were compared in 32 independent cohorts with 3474 patients.
RESULTS
Methylation-specific PCR (MSP) and pyrosequencing (PSQ) techniques were more prognostic than immunohistochemistry for MGMT protein, and PSQ is a slightly better predictor than MSP.
CONCLUSIONS
We cannot draw strong conclusions about use of frozen tissue vs formalin-fixed paraffin-embedded in MSP and PSQ. Also, our meta-analysis does not provide strong evidence about the best CpG sites or threshold. MSP has been studied mainly for CpG sites 76-80 and 84-87 and PSQ at CpG sites ranging from 72 to 95. A cutoff threshold of 9% for CpG sites 74-78 performed better than higher thresholds of 28% or 29% in 2 of the 3 good-quality studies. About 190 studies were identified presenting HRs from survival analysis in patients in which MGMT methylation was measured by 1 technique only.
Topics: Antineoplastic Agents, Alkylating; Brain Neoplasms; DNA Methylation; DNA Modification Methylases; DNA Repair Enzymes; Glioblastoma; Glioma; Humans; Methylation; Promoter Regions, Genetic; Temozolomide; Tumor Suppressor Proteins
PubMed: 34467991
DOI: 10.1093/neuonc/noab105 -
AJNR. American Journal of Neuroradiology Aug 2018() promoter methylation status has been reported as a prognostic biomarker in clinical trials. (Meta-Analysis)
Meta-Analysis
BACKGROUND
() promoter methylation status has been reported as a prognostic biomarker in clinical trials.
PURPOSE
Our aim was to systematically evaluate imaging features of promoter methylated glioblastoma and to determine the diagnostic performance of MR imaging for prediction of promoter methylation in patients with newly diagnosed glioblastoma.
DATA SOURCES
A computerized search of Ovid MEDLINE and EMBASE up to February 27, 2018, was conducted.
STUDY SELECTION
We selected studies evaluating imaging features of promoter methylated glioblastoma and the diagnostic performance of MR imaging for prediction of promoter methylation.
DATA ANALYSIS
Pooled estimates of sensitivity and specificity were calculated using a hierarchic logistic regression model. Meta-regression and sensitivity analysis were performed.
DATA SYNTHESIS
Twenty-two articles including 2199 patients were included. promoter methylated glioblastoma is likely to show less edema, high ADC, and low perfusion. Ten articles including 753 patients were included in the meta-analysis. The summary sensitivity was 79% (95% CI, 72%-85%), and the summary specificity was 78% (95% CI, 71%-84%). In the meta-regression, promoter methylation and mean age were associated with heterogeneity. Sensitivity analysis excluding 1 study resolved the heterogeneity.
LIMITATIONS
Included studies used a variety of different MR imaging techniques to predict promoter methylation.
CONCLUSIONS
promotor methylated glioblastoma is likely to show less aggressive imaging features than promotor unmethylated glioblastoma. Despite the variety of different MR imaging techniques used, MR imaging in patients with newly diagnosed glioblastoma was shown to have the potential to predict promoter methylation noninvasively.
Topics: Aged; Brain Neoplasms; DNA Methylation; DNA Modification Methylases; DNA Repair Enzymes; Female; Glioblastoma; Humans; Magnetic Resonance Imaging; Male; Middle Aged; Neuroimaging; Promoter Regions, Genetic; Sensitivity and Specificity; Tumor Suppressor Proteins
PubMed: 30002055
DOI: 10.3174/ajnr.A5711 -
Clinical Epigenetics May 2020Assessing long-term health effects from a potentially harmful environment is challenging. Endocrine-disrupting compounds (EDCs) have become omnipresent in our...
Assessing long-term health effects from a potentially harmful environment is challenging. Endocrine-disrupting compounds (EDCs) have become omnipresent in our environment. Individuals may or may not experience clinical health issues from being exposed to the increasing environmental pollution in daily life, but an issue of high concern is that also the non-exposed progeny may encounter consequences of these ancestral exposures. Progress in understanding epigenetic mechanisms opens new perspectives to estimate the risk of man-made EDCs. However, the field of epigenetic toxicology is new and its application in public health or in the understanding of disease etiology is almost non-existent, especially if it concerns future generations. In this review, we investigate the literature on transgenerational inheritance of diseases, published in the past 10 years. We question whether persistent epigenetic changes occur in the male germ line after exposure to synthesized EDCs. Our systematic search led to an inclusion of 43 articles, exploring the effects of commonly used synthetic EDCs, such as plasticizers (phthalates and bisphenol A), pesticides (dichlorodiphenyltrichloroethane, atrazine, vinclozin, methoxychlor), dioxins, and polycyclic aromatic hydrocarbons (PAHs, such as benzo(a)pyrene). Most studies found transgenerational epigenetic effects, often linked to puberty- or adult-onset diseases, such as testicular or prostate abnormalities, metabolic disorders, behavioral anomalies, and tumor development. The affected epigenetic mechanisms included changes in DNA methylation patterns, transcriptome, and expression of DNA methyltransferases. Studies involved experiments in animal models and none were based on human data. In the future, human studies are needed to confirm animal findings. If not transgenerational, at least intergenerational human studies and studies on EDC-induced epigenetic effects on germ cells could help to understand early processes of inheritance. Next, toxicity tests of new chemicals need a more comprehensive approach before they are introduced on the market. We further point to the relevance of epigenetic toxicity tests in regard to public health of the current population but also of future generations. Finally, this review sheds a light on how the interplay of genetics and epigenetics may explain the current knowledge gap on transgenerational inheritance.
Topics: Animals; Atrazine; Benzhydryl Compounds; Benzo(a)pyrene; DDT; Dioxins; Endocrine Disruptors; Epigenesis, Genetic; Male; Mammals; Mice; Paternal Inheritance; Phenols; Phthalic Acids
PubMed: 32398147
DOI: 10.1186/s13148-020-00845-1 -
Zhejiang Da Xue Xue Bao. Yi Xue Ban =... Mar 2015To evaluate the effects of DNMT3A gene mutation on prognosis of patients with acute myeloid leukemia (AML) by a meta-analysis. (Meta-Analysis)
Meta-Analysis
OBJECTIVE
To evaluate the effects of DNMT3A gene mutation on prognosis of patients with acute myeloid leukemia (AML) by a meta-analysis.
METHODS
Methods of Cochrane systematic review was followed by 7 databases,including PubMed, Embase, Ovid, CNKI, CBM, WanFang Data and VIP, were searched for peer-reviewed articles related to DNMT3A gene mutations and prognosis of patients with AML.Then manual retrieval was applied into literature references. After the evaluation of quality and extract of clinical trialliterature data, Stata 11.0 was employed to perform meta-analysis.
RESULTS
Seven randomized controlled trials involving 1493 cases were included in the meta-analysis. The prognosis of patients with DNMT3A mutations and without DNMT3A mutations was compared. There was no statistically significant difference in complete remission(CR) rate (OR=1.034, 95%CI: 0.596~1.796, P=0.905 between two groups, but the overall survival (OS(HR=1.990, 95%CI: 1.463~2.510, P=0.000 and disease free survival (DFS) (HR= 2.840, 95%CI: 1.063~4.613, P=0.002) of patients without DNMT3A mutations were longer than those with DNMT3A mutation.
CONCLUSION
DNMT3A gene mutation is an independent risk factor of poor prognosis of patients with acute myeloid leukemia.
Topics: DNA (Cytosine-5-)-Methyltransferases; DNA Methyltransferase 3A; Humans; Leukemia, Myeloid, Acute; Mutation; Prognosis; Risk Factors
PubMed: 26038140
DOI: 10.3785/j.issn.1008-9292.2015.03.013