-
Cell Death & Disease Apr 2024N6-methyladenosine (m6A) methylation, a prevalent eukaryotic post-transcriptional modification, is involved in multiple biological functions, including mediating... (Review)
Review
N6-methyladenosine (m6A) methylation, a prevalent eukaryotic post-transcriptional modification, is involved in multiple biological functions, including mediating variable splicing, RNA maturation, transcription, and nuclear export, and also is vital for regulating RNA translation, stability, and cytoplasmic degradation. For example, m6A methylation can regulate pre-miRNA expression by affecting both splicing and maturation. Non-coding RNA (ncRNA), which includes microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs), does not encode proteins but has powerful impacts on transcription and translation. Conversely, ncRNAs may impact m6A methylation by affecting the expression of m6A regulators, including miRNAs targeting mRNA of m6A regulators, or lncRNAs, and circRNAs, acting as scaffolds to regulate transcription of m6A regulatory factors. Dysregulation of m6A methylation is common in urinary tumors, and the regulatory role of ncRNAs is also important for these malignancies. This article provides a systematic review of the role and mechanisms of action of m6A methylation and ncRNAs in urinary tumors.
Topics: Humans; RNA, Long Noncoding; RNA, Circular; RNA, Untranslated; Neoplasms; MicroRNAs; Adenosine
PubMed: 38632251
DOI: 10.1038/s41419-024-06664-z -
European Journal of Cancer (Oxford,... Nov 2022Grading and classification of IDH-mutant astrocytomas has shifted from solely histology towards histology combined with molecular diagnostics. In this systematic review,... (Review)
Review
BACKGROUND
Grading and classification of IDH-mutant astrocytomas has shifted from solely histology towards histology combined with molecular diagnostics. In this systematic review, we give an overview of all currently known clinically relevant molecular markers within IDH-mutant astrocytomas grade 2 to 4.
METHODS
A literature search was performed in five electronic databases for English original papers on patient outcome with respect to a molecular marker as determined by DNA/RNA sequencing, micro-arrays, or DNA methylation profiling in IDH-mutant astrocytomas grade 2 to 4. Papers were included if molecular diagnostics were performed on tumour tissue of at least 15 IDH-mutant astrocytoma patients, and if the investigated molecular markers were not limited to the diagnostic markers MGMT, ATRX, TERT, and/or TP53.
RESULTS
The literature search identified 4508 unique articles, published between August 2012 and December 2021, of which ultimately 44 articles were included. Numerous molecular markers from these papers were significantly correlated to patient outcome. The associations between patient outcome and non-canonical IDH mutations, PI3K mutations, high expression of MSH2, high expression of RAD18, homozygous deletion of CDKN2A/B, amplification of PDGFRA, copy number neutral loss of chromosomal arm 17p, loss of chromosomal arm 19q, the G-CIMP-low DNA methylation cluster, high total CNV, and high tumour mutation burden were confirmed in multiple studies.
CONCLUSIONS
Multiple genetic and epigenetic markers are associated with survival in IDH-mutant astrocytoma patients. Commonly affected are the RB signalling pathway, the RTK-PI3K-mTOR signalling pathway, genomic stability markers, and (epigenetic) gene regulation.
Topics: Astrocytoma; Biomarkers, Tumor; Brain Neoplasms; DNA; DNA-Binding Proteins; Homozygote; Humans; Isocitrate Dehydrogenase; Lymphoma, Follicular; MutS Homolog 2 Protein; Mutation; Phosphatidylinositol 3-Kinases; Sequence Deletion; TOR Serine-Threonine Kinases; Ubiquitin-Protein Ligases
PubMed: 36152406
DOI: 10.1016/j.ejca.2022.08.016 -
Advances in Hematology 2024Epigenetic regulation has been thoroughly investigated in recent years and has emerged as an important aspect of chronic lymphocytic leukemia (CLL) biology.... (Review)
Review
Epigenetic regulation has been thoroughly investigated in recent years and has emerged as an important aspect of chronic lymphocytic leukemia (CLL) biology. Characteristic aberrant features such as methylation patterns and global DNA hypomethylation were the early findings of the research during the last decades. The investigation in this field led to the identification of a large number of genes where methylation features correlated with important clinical and laboratory parameters. Gene-specific analyses investigated methylation in the gene body enhancer regions as well as promoter regions. The findings included genes and proteins involved in key pathways that play central roles in the pathophysiology of the disease. Τhe application of these findings beyond the theoretical understanding can not only lead to the creation of prognostic and predictive models and scores but also to the design of novel therapeutic agents. The following is a review focusing on the present knowledge about single gene/gene promoter methylation or mRNA expression in CLL cases as well as records of older data that have been published in past papers.
PubMed: 38435839
DOI: 10.1155/2024/1370364 -
Cancers Aug 2022The objective of this systematic review was to summarize our current knowledge of the role of immunohistochemistry (IHC) markers for identifying mismatch... (Review)
Review
The objective of this systematic review was to summarize our current knowledge of the role of immunohistochemistry (IHC) markers for identifying mismatch repair-deficient (MMRd) tumors in endometrial cancer (EC). Identification of MMRd tumors, which occur in 13% to 30% of all ECs, has become critical for patients with colorectal and endometrial cancer for therapeutic management, clinical decision making, and prognosis. This review was conducted by two authors applying the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines using the following terms: "immunohistochemistry and microsatellite instability endometrial cancer" or "immunohistochemistry and mismatch repair endometrial cancer" or "immunohistochemistry and mismatch repair deficient endometrial cancer". Among 596 retrieved studies, 161 fulfilled the inclusion criteria. Articles were classified and presented according to their interest for the diagnosis, prognosis, and theragnostics for patients with MMRd EC. We identified 10, 18, and 96 articles using IHC expression of two, three, or four proteins of the MMR system (MLH1, MSH2, MHS6, and PMS2), respectively. MLH1 promoter methylation was analyzed in 57 articles. Thirty-four articles classified MMRd tumors with IHC markers according to their prognosis in terms of recurrence-free survival (RFS), overall survival (OS), stage, grade, and lymph node invasion. Theragnostics were studied in eight articles underlying the important concentration of PD-L1 in MMRd EC. Even though the role of IHC has been challenged, it represents the most common, robust, and cheapest method for diagnosing MMRd tumors in EC and is a valuable tool for exploring novel biotherapies and treatment modalities.
PubMed: 35954447
DOI: 10.3390/cancers14153783 -
International Journal of Molecular... May 2023This systematic review and thematic analysis critically evaluated gene therapy trials in amyotrophic lateral sclerosis, haemoglobinopathies, immunodeficiencies,... (Review)
Review
This systematic review and thematic analysis critically evaluated gene therapy trials in amyotrophic lateral sclerosis, haemoglobinopathies, immunodeficiencies, leukodystrophies, lysosomal storage disorders and retinal dystrophies and extrapolated the key clinical findings to individuals with Rett syndrome (RTT). The PRISMA guidelines were used to search six databases during the last decade, followed by a thematic analysis to identify the emerging themes. Thematic analysis across the different disorders revealed four themes: (I) Therapeutic time window of gene therapy; (II) Administration and dosing strategies for gene therapy; (III) Methods of gene therapeutics and (IV) Future areas of clinical interest. Our synthesis of information has further enriched the current clinical evidence base and can assist in optimising gene therapy and gene editing studies in individuals with RTT, but it would also benefit when applied to other disorders. The findings suggest that gene therapies have better outcomes when the brain is not the primary target. Across different disorders, early intervention appears to be more critical, and targeting the pre-symptomatic stage might prevent symptom pathology. Intervention at later stages of disease progression may benefit by helping to clinically stabilise patients and preventing disease-related symptoms from worsening. If gene therapy or editing has the desired outcome, older patients would need concerted rehabilitation efforts to reverse their impairments. The timing of intervention and the administration route would be critical parameters for successful outcomes of gene therapy/editing trials in individuals with RTT. Current approaches also need to overcome the challenges of MeCP2 dosing, genotoxicity, transduction efficiencies and biodistribution.
Topics: Humans; Rett Syndrome; Gene Editing; Tissue Distribution; Methyl-CpG-Binding Protein 2; Brain; Genetic Therapy
PubMed: 37240368
DOI: 10.3390/ijms24109023 -
World Journal of Gastroenterology Nov 2013To assess diagnostic accuracy of Ras association domain family 1A (RASSF1A) promoter methylation in body fluids (serum, plasma and whole blood) for hepatocellular... (Meta-Analysis)
Meta-Analysis Review
AIM
To assess diagnostic accuracy of Ras association domain family 1A (RASSF1A) promoter methylation in body fluids (serum, plasma and whole blood) for hepatocellular carcinoma (HCC).
METHODS
Relative information about study characteristics and incidence of RASSF1A methylation was collected. Quality of all included studies was evaluated by Quality Assessment of Diagnostic Accuracy Studies-2. Sensitivity and specificity were pooled using a random-effect model, and a summary receiver operating characteristic curve was used to demonstrate the overall diagnostic performance. Positive likelihood ratio (PLR), negative likelihood ratio (NLR), and diagnostic odds ratio (DOR) with 95%CI were also calculated. Meta-regression was applied to analyze observed heterogeneity, and Deeks' test was performed to detect publication bias.
RESULTS
After a systematic literature review, seven studies with a total of 302 cases of HCC and 250 cases of chronic liver diseases were included in the analysis. The pooled sensitivity and specificity were 0.70 (95%CI: 0.49-0.85) and 0.72 (95%CI: 0.54-0.85), respectively. The PLR was 2.51 (95%CI: 1.64-3.86), NLR was 0.41 (95%CI: 0.25-0.68), and DOR was 6.13 (95%CI: 3.17-11.84). The χ(2) values of sensitivity, specificity, PLR, NLR and DOR were 59.41 (P < 0.001), 50.50 (P < 0.001), 17.40 (P = 0.010), 31.24 (P < 0.001) and 80.51 (P < 0.001), respectively. The area under the curve was 0.77 (95%CI: 0.73-0.81). Three factors were analyzed by univariate meta-regression and none was significant to interpret the observed heterogeneity (P > 0.05). No significant publication bias was detected by Deeks' test (P = 0.346).
CONCLUSION
We showed the potential diagnostic value of RASSF1A methylation in body fluids in HCC patients and it may improve diagnostic accuracy combined with the α-fetoprotein test.
Topics: Carcinoma, Hepatocellular; Chi-Square Distribution; DNA Methylation; Genetic Predisposition to Disease; Genetic Testing; Humans; Likelihood Functions; Liver Neoplasms; Odds Ratio; Phenotype; Predictive Value of Tests; Prognosis; Promoter Regions, Genetic; ROC Curve; Risk Factors; Tumor Suppressor Proteins; alpha-Fetoproteins
PubMed: 24222965
DOI: 10.3748/wjg.v19.i41.7189 -
The Yale Journal of Biology and Medicine Dec 2021Williams Syndrome (WS) is a rare genetic multisystem disorder that occurs because of a deletion of approximately 25 genes in the 7q11.23 chromosome region. This causes... (Review)
Review
Williams Syndrome (WS) is a rare genetic multisystem disorder that occurs because of a deletion of approximately 25 genes in the 7q11.23 chromosome region. This causes dysmorphic facial appearances, multiple congenital cardiovascular defects, delayed motor skills, and abnormalities in connective tissues and the endocrine system. The patients are mostly diagnosed with mild to moderate mental retardation, however, they have a hyper sociable, socially dis-inhibited, and outgoing personality, empathetic behavior, and are highly talkative. Oxytocin (OT), a neuropeptide synthesized at the hypothalamus, plays an important role in cognition and behavior, and is thought to be affecting WS patients' attitudes at its different amounts. Oxytocin receptor gene (), on chromosome 3p25.3, is considered regulating oxytocin receptors, via which OT exerts its effect. WS is a crucial disorder to understand gene, hormone, brain, and behavior associations in terms of sociality and neuropsychiatric conditions. Alterations to the WS gene region offer an opportunity to deepen our understandings of autism spectrum disorder, schizophrenia, anxiety, or depression. We aim to systematically present the data available of OT/ regulation and expression, and the evidence for whether these mechanisms are dysregulated in WS. These results are important, as they predict strong epigenetic control over social behavior by methylation, single nucleotide polymorphisms, and other alterations. The comparison and collaboration of these studies may help to establish a better treatment or management approach for patients with WS if backed up with future research.
Topics: Autism Spectrum Disorder; Humans; Oxytocin; Receptors, Oxytocin; Social Behavior; Williams Syndrome
PubMed: 34970101
DOI: No ID Found -
Porto Biomedical Journal 2016Single nucleotide polymorphisms (SNPs) in DNA methyltransferases (DNMTs) modulate protein expression and affect DNA methylation.Aberrant DNA methylation, have been...
HIGHLIGHTS
Single nucleotide polymorphisms (SNPs) in DNA methyltransferases (DNMTs) modulate protein expression and affect DNA methylation.Aberrant DNA methylation, have been associated with gastric carcinogenesis.DNMT2 rs11254413 is associated with protection for GC development.DNMT3A rs7560488, DNMT3A rs36012910 and, specially, DNMT1 rs16999593 are associated with increased susceptibility for GC development.
ABSTRACT
Epigenetics alterations, including aberrant DNA methylation, have been associated with gastric carcinogenesis. Single nucleotide polymorphisms (SNPs) in DNA methyltransferases (DNMTs) may influence protein expression and therefore affect DNA regulation and susceptibility for Gastric Cancer (GC).We have performed a systematic review and meta-analysis involving 11 studies and a total of 24 SNPs in DNMTs were analyzed. According to literature, only 4 SNPs, DNMT1 rs16999593, DNMT2 rs11254413 and DNMT3A rs7560488 and DNMT3A rs36012910, were associated with GC. DNMT1 rs16999593 and DNMT3A rs7560488C allele and DNMT3A rs36012910 G allele showed an increased risk for GC. On the other hand, DNMT2 rs11254413 G allele presented a protective effect for GC. Additionally, the meta-analysis evaluated the SNPs analyzed in more than one study ( = 6). Results revealed that only DNMT1 rs16999593 had a statistically significant association with GC development (OR = 1.31; 95% CI = 1.08-1.60; = 0.006 for TC + CC genotypes).Our study suggests that DNMT2 rs11254413, DNMT3A rs7560488, DNMT3A rs36012910 and, specially, DNMT1 rs16999593 may have an association with GC development. Nevertheless, further studies are need using different populations to clarify this association with GC risk.
PubMed: 32258570
DOI: 10.1016/j.pbj.2016.10.005 -
Frontiers in Cardiovascular Medicine 2022Myocardial infarction is the leading cause of death and disability worldwide, and the development of new treatments can help reduce the size of myocardial infarction and...
Myocardial infarction is the leading cause of death and disability worldwide, and the development of new treatments can help reduce the size of myocardial infarction and prevent adverse cardiovascular events. Cardiac repair after myocardial infarction can effectively remove necrotic tissue, induce neovascularization, and ultimately replace granulation tissue. Cardiac inflammation is the primary determinant of whether beneficial cardiac repair occurs after myocardial infarction. Immune cells mediate inflammatory responses and play a dual role in injury and protection during cardiac repair. After myocardial infarction, genetic ablation or blocking of anti-inflammatory pathways is often harmful. However, enhancing endogenous anti-inflammatory pathways or blocking endogenous pro-inflammatory pathways may improve cardiac repair after myocardial infarction. A deficiency of neutrophils or monocytes does not improve overall cardiac function after myocardial infarction but worsens it and aggravates cardiac fibrosis. Several factors are critical in regulating inflammatory genes and immune cells' phenotypes, including DNA methylation, histone modifications, and non-coding RNAs. Therefore, strict control and timely suppression of the inflammatory response, finding a balance between inflammatory cells, preventing excessive tissue degradation, and avoiding infarct expansion can effectively reduce the occurrence of adverse cardiovascular events after myocardial infarction. This article reviews the involvement of neutrophils, monocytes, macrophages, and regulatory T cells in cardiac repair after myocardial infarction. After myocardial infarction, neutrophils are the first to be recruited to the damaged site to engulf necrotic cell debris and secrete chemokines that enhance monocyte recruitment. Monocytes then infiltrate the infarct site and differentiate into macrophages and they release proteases and cytokines that are harmful to surviving myocardial cells in the pre-infarct period. As time progresses, apoptotic neutrophils are cleared, the recruitment of anti-inflammatory monocyte subsets, the polarization of macrophages toward the repair phenotype, and infiltration of regulatory T cells, which secrete anti-inflammatory factors that stimulate angiogenesis and granulation tissue formation for cardiac repair. We also explored how epigenetic modifications regulate the phenotype of inflammatory genes and immune cells to promote cardiac repair after myocardial infarction. This paper also elucidates the roles of alarmin S100A8/A9, secreted frizzled-related protein 1, and podoplanin in the inflammatory response and cardiac repair after myocardial infarction.
PubMed: 36698953
DOI: 10.3389/fcvm.2022.1077290 -
Techniques in Coloproctology Jul 2018The purpose of this systematic review was to compare the diagnostic ability of blood markers for colorectal cancer (CRC). A systematic review of the literature for... (Review)
Review
The purpose of this systematic review was to compare the diagnostic ability of blood markers for colorectal cancer (CRC). A systematic review of the literature for diagnostic blood markers for primary human colorectal cancer over the last 5 years was performed. The primary outcome was to assess the diagnostic ability of these markers in diagnosing colorectal cancer. The secondary outcome was to see whether the marker was compared to other markers. The tertiary outcome was to assess diagnostic ability in early versus late CRC, including stage IV disease. We identified 51 studies (29 prospective, 14 retrospective, and 8 meta-analyses). The markers were divided in broadly four groups: nucleic acids (RNA/DNA/messenger RNA/microRNAs), cytokines, antibodies, and proteins. The most promising circulating markers identified among the nucleid acids were NEAT_v2 non-coding RNA, SDC2 methylated DNA, and SEPT9 methylated DNA. The most promising cytokine to detect CRC was interleukin 8, and the most promising circulating proteins were CA11-19 glycoprotein and DC-SIGN/DC-SIGNR. Sensitivities of these markers for detecting primary colorectal carcinoma ranged from 70 to 98% and specificities from 84 to 98.7%. The best studied blood marker was SEPT9 methylated DNA, which showed great variability with sensitivities ranging from 48.2 to 95.6% and specificities from 80 to 98.9%, making its clinical applicability challenging. If combined with fecal immunochemical test (FIT), the sensitivity improved from 78 to 94% in detecting CRC. Methylated SEPT9, methylated SDC2, and -SIGN/DC-SIGNR protein had better sensitivity and specificity than CEA or CA 19-9. With the exception of SEPT9 which is currently being implemented as a screening test for CRC all other markers lacked reproducibility and standardization and were studied in relatively small population samples.
Topics: Adult; Biomarkers, Tumor; Colorectal Neoplasms; DNA Methylation; Early Detection of Cancer; Female; Humans; Male; Meta-Analysis as Topic; Middle Aged; Neoplasm Staging; Prospective Studies; RNA, Long Noncoding; Reproducibility of Results; Retrospective Studies; Sensitivity and Specificity; Septins; Syndecan-2
PubMed: 30022330
DOI: 10.1007/s10151-018-1820-3