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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 -
Iranian Journal of Public Health Dec 2021The tumor suppressor genes play a critical role in cellular and molecular mechanisms such as cell cycle processes, cell differentiation and apoptosis. Aberrant DNA... (Review)
Review
BACKGROUND
The tumor suppressor genes play a critical role in cellular and molecular mechanisms such as cell cycle processes, cell differentiation and apoptosis. Aberrant DNA methylation of tumor suppressor genes and subsequent gene expression changes have shown to be involved in the initiation and progression of various malignancies including thyroid malignancies. In this review, we investigated what is known about the impact of promoter hypermethylation on the key tumor suppressor genes known to be involved in cell growth and/or apoptosis of thyroid cancer.
METHODS
The most important databases were searched for research articles until June 2020 to identify reported tumor suppressor genes that are modulated by methylation modulation changes in thyroid carcinoma. Following the inclusion and exclusion criteria, 26 studies were reviewed using the full text to meet the inclusion and exclusion criteria.
RESULTS
The tumor suppressor genes reviewed here are suggestive biomarkers and potential targetable drugs. Inactivation of , , , and through aberrant epigenetic methylation could activate BRAF/MEK/ERK kinase pathways with potential clinical implications in thyroid cancer patients. and could suppress cell cycle and induce apoptosis in malignant cells. and could prevent angiogenesis and invasion through PIP3 pathway and arrest VEFG activity.
CONCLUSION
The methylation status of key genes in various types of thyroid malignancies could be used in early diagnosis as well as differentiation of malignant and benign thyroid. This is valuable in drug repurposing and discovering alternative treatments or preventions in thyroid cancer.
PubMed: 36317025
DOI: 10.18502/ijph.v50i12.7928 -
BMC Pulmonary Medicine Mar 2017Epigenetic variations in peripheral blood have potential as biomarkers for disease. This systematic review assesses the association of lung function and chronic... (Review)
Review
BACKGROUND
Epigenetic variations in peripheral blood have potential as biomarkers for disease. This systematic review assesses the association of lung function and chronic obstructive pulmonary disease (COPD) with DNA methylation profiles in peripheral blood from population-based studies.
METHODS
Online databases Medline, Embase, and Web of Science were searched. Google Scholar was searched to identify grey literature. After removing duplicate articles, 1155 articles were independently screened by two investigators. Peer reviewed reports on population-based studies that examined peripheral blood DNA methylation in participants with measured lung function (FEV1, FEV1/FVC ratio) or known COPD status were selected for full-text review. Six articles were suitable for inclusion. Information regarding study characteristics, designs, methodologies and conclusions was extracted. A narrative synthesis was performed based on published results.
RESULTS
Three of the six articles assessed the association of COPD with DNA methylation, and two of these also included associations with lung function. Overall, five reports examined the association of lung function with DNA methylation profiles. Five of the six articles reported 'significant' results. However, no consistent CpG sites were identified across studies for COPD status or lung function values.
CONCLUSIONS
DNA methylation patterns in peripheral blood from individuals with reduced lung function or COPD may be different to those in people with normal lung function. However, this systematic review did not find any consistent associations of lung function or COPD with differentially methylated CpG sites. Large studies with a longitudinal design to address reverse causality may prove a more fruitful area of research.
TRIAL REGISTRATION
PROSPERO 2016: CRD42016037352 .
Topics: DNA Methylation; Epigenesis, Genetic; Humans; Pulmonary Disease, Chronic Obstructive; Respiratory Function Tests
PubMed: 28320365
DOI: 10.1186/s12890-017-0397-3 -
International Journal of Colorectal... Feb 2021Methylated cell-free DNA in liquid biopsies are promising non-invasive biomarkers for colorectal cancer (CRC). Optimal markers would have high sensitivity and... (Review)
Review
PURPOSE
Methylated cell-free DNA in liquid biopsies are promising non-invasive biomarkers for colorectal cancer (CRC). Optimal markers would have high sensitivity and specificity for early detection of CRC and could be detected in more than one type of material from the patient. We systematically reviewed the literature on DNA methylation markers of colorectal cancer, detected in more than one type of material, regarding their potential as contributors to a panel for screening and follow-up of CRC.
METHODS
The databases MEDLINE, Web of Science, and Embase were systematically searched. Data extraction and review was performed by two authors independently. Agreement between methylation status in tissue and other materials (blood/stool/urine) was analyzed using the McNemar test and Cohen's kappa.
RESULTS
From the 51 included studies, we identified seven single markers with sensitivity ≥ 75% and specificity ≥ 90% for CRC. We also identified one promising plasma panel and two stool panels. The correspondence of methylation status was evaluated as very good for four markers, but only marginal for most of the other markers investigated (12 of 21).
CONCLUSION
The included studies reported only some of the variables and markers of interest and included few patients. Hence, a meta-analysis was not possible at this point. Larger, prospective studies must be designed to study the discordant detection of markers in tissue and liquid biopsies. When reporting their findings, such studies should use a standardized format.
Topics: Biomarkers, Tumor; Colorectal Neoplasms; DNA Methylation; Early Detection of Cancer; Humans; Prospective Studies
PubMed: 33030559
DOI: 10.1007/s00384-020-03757-x -
Genes Feb 2023Chronic pain represents a major global health issue in terms of psycho-physiological, therapeutic, and economic burden, not limited to adults but also to the pediatric... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND AND OBJECTIVE
Chronic pain represents a major global health issue in terms of psycho-physiological, therapeutic, and economic burden, not limited to adults but also to the pediatric age. Despite its great impact, its molecular mechanisms have still not been completely unraveled. Focusing on the impact of epigenetics in the pain complex trait, we assessed the association between chronic pain and the methylation pattern of TRPA1, a key gene related to pain sensitivity.
METHODS
We conducted a systematic review retrieving articles from three different databases. After deduplication, 431 items were subjected to manual screening, and then 61 articles were selected and screened again. Of these, only six were maintained for meta-analysis and analyzed using specific R packages.
RESULTS
Six articles were divided into two groups (group 1: comparison of mean methylation levels between healthy subjects and patients with chronic pain; group 2: correlation between mean methylation levels and pain sensation). A non-significant mean difference was obtained from the analysis of group 1 with a value of 3.97 (95% C.I. -7.79; 15.73). Analysis of group 2 showed a high level of variability between studies (correlation = 0.35, 95% C.I. -0.12; 0.82) due to their heterogeneity (I = 97%, < 0.01).
CONCLUSIONS
Despite the high variability observed in the different studies analyzed, our results suggest that hypermethylation and increased pain sensitivity could be connected, possibly due to the variation of TRPA1 expression.
Topics: Adult; Child; Humans; Ankyrins; Chronic Pain; DNA Methylation; Epigenesis, Genetic; TRPA1 Cation Channel
PubMed: 36833338
DOI: 10.3390/genes14020411 -
Neuroscience and Biobehavioral Reviews Apr 2023Epigenomic modifications of the brain-derived neurotrophic factor (BDNF) gene have been postulated to underlie the pathogenesis of neurodevelopmental, psychiatric, and... (Review)
Review
Epigenomic modifications of the brain-derived neurotrophic factor (BDNF) gene have been postulated to underlie the pathogenesis of neurodevelopmental, psychiatric, and neurological conditions. This systematic review summarizes current evidence investigating the association of BDNF epigenomic modifications (DNA methylation, non-coding RNA, histone modifications) with brain-related phenotypes in humans. A novel contribution is our creation of an open access web-based application, the BDNF DNA Methylation Map, to interactively visualize specific positions of CpG sites investigated across all studies for which relevant data were available. Our literature search of four databases through September 27, 2021 returned 1701 articles, of which 153 met inclusion criteria. Our review revealed exceptional heterogeneity in methodological approaches, hindering the identification of clear patterns of robust and/or replicated results. We summarize key findings and provide recommendations for future epigenomic research. The existing literature appears to remain in its infancy and requires additional rigorous research to fulfill its potential to explain BDNF-linked risk for brain-related conditions and improve our understanding of the molecular mechanisms underlying their pathogenesis.
Topics: Humans; Brain; Brain-Derived Neurotrophic Factor; DNA Methylation; Epigenomics; Phenotype
PubMed: 36764636
DOI: 10.1016/j.neubiorev.2023.105078 -
PloS One 2017One of the critical mechanisms of gastrointestinal cancer pathogenesis is the silencing of death associated protein kinase 1 (DAPK1), which could be caused by aberrant... (Meta-Analysis)
Meta-Analysis Review
OBJECTIVE
One of the critical mechanisms of gastrointestinal cancer pathogenesis is the silencing of death associated protein kinase 1 (DAPK1), which could be caused by aberrant methylation of the promoter. However, the relationship between DAPK1 methylation and the risk of gastrointestinal cancer is still controversial. Hence, we conducted this study to determine the potential correlation.
METHODS
Eligible publications were searched in the Pubmed, Embase, and Cochrane Library through November 2016 according to the inclusion criteria and exclusion criteria. Revman 5.3 and Stata 12.0 software were used to analyze the relevant data regarding the association between the frequency of DAPK1 methylation and gastrointestinal cancer.
RESULTS
A total of 22 studies with 2406 patients were included in this meta analysis. Methylation of DAPK1 was positively related with the risk of gastrointestinal cancer (odds ratio [OR] = 5.35, 95% confidence interval [CI]: 2.76-10.38, P<0.00001, random effects model). The source of heterogeneity was analyzed by sensitivity analysis and subgroup analysis. After omitting one heterogeneous study, the I2 decreased and the OR increased in pooled analysis. Also, the heterogeneity decreased most significantly in the subgroup of studies that had a sample size of less than 60 cases. Then, the correlations between DAPK1 methylation and clinicopathological features of gastrointestinal cancer were assessed. DAPK1 methylation was positively correlated with the lymph node (N) stage (positive vs. negative, OR = 1.45, 95%CI: 1.01-2.06, P = 0.04, fixed effects model) and poor differentiation (OR = 1.55, 95%CI: 1.02-2.35, P = 0.04, fixed effects model) in gastric cancer, and the association was significant among Asian patients. However, among cases of gastrointestinal cancer, the association between DAPK1 methylation and tumor (T) stage, N stage, distant metastasis (M) stage, and cancer differentiation were not statistically significant.
CONCLUSIONS
DAPK1 methylation is a potential biomarker for the early diagnosis of gastrointestinal cancer. Further analysis of the clinicopathological features indicated that aberrant methylation of DAPK1 is positively associated with the tumorigenesis of gastrointestinal cancer, and metastasis of gastric cancer.
Topics: DNA Methylation; Death-Associated Protein Kinases; Gastrointestinal Neoplasms; Gene Expression Regulation, Neoplastic; Genetic Predisposition to Disease; Humans; Risk Factors
PubMed: 28934284
DOI: 10.1371/journal.pone.0184959 -
Advances in Nutrition (Bethesda, Md.) Nov 2023Accumulation of deoxyribonucleic acid (DNA) damage diminishes cellular health, increases risk of developmental and degenerative diseases, and accelerates aging.... (Review)
Review
Protective Effects of Micronutrient Supplements, Phytochemicals and Phytochemical-Rich Beverages and Foods Against DNA Damage in Humans: A Systematic Review of Randomized Controlled Trials and Prospective Studies.
Accumulation of deoxyribonucleic acid (DNA) damage diminishes cellular health, increases risk of developmental and degenerative diseases, and accelerates aging. Optimizing nutrient intake can minimize accrual of DNA damage. The objectives of this review are to: 1) assemble and systematically analyze high-level evidence for the effect of supplementation with micronutrients and phytochemicals on baseline levels of DNA damage in humans, and 2) use this knowledge to identify which of these essential micronutrients or nonessential phytochemicals promote DNA integrity in vivo in humans. We conducted systematic literature searches of the PubMed database to identify interventional, prospective, cross-sectional, or in vitro studies that explored the association between nutrients and established biomarkers of DNA damage associated with developmental and degenerative disease risk. Biomarkers included lymphocyte chromosome aberrations, lymphocyte and buccal cell micronuclei, DNA methylation, lymphocyte/leukocyte DNA strand breaks, DNA oxidation, telomere length, telomerase activity, and mitochondrial DNA mutations. Only randomized, controlled interventions and uncontrolled longitudinal intervention studies conducted in humans were selected for evaluation and data extraction. These studies were ranked for the quality of their study design. In all, 96 of the 124 articles identified reported studies that achieved a quality assessment score ≥ 5 (from a maximum score of 7) and were included in the final review. Based on these studies, nutrients associated with protective effects included vitamin A and its precursor β-carotene, vitamins C, E, B1, B12, folate, minerals selenium and zinc, and phytochemicals such as curcumin (with piperine), lycopene, and proanthocyanidins. These findings highlight the importance of nutrients involved in (i) DNA metabolism and repair (folate, vitamin B, and zinc) and (ii) prevention of oxidative stress and inflammation (vitamins A, C, E, lycopene, curcumin, proanthocyanidins, selenium, and zinc). Supplementation with certain micronutrients and their combinations may reduce DNA damage and promote cellular health by improving the maintenance of genome integrity.
Topics: Humans; Prospective Studies; Selenium; Lycopene; Cross-Sectional Studies; Curcumin; Proanthocyanidins; Randomized Controlled Trials as Topic; Vitamins; Vitamin A; Micronutrients; Folic Acid; Zinc; Beverages; Phytochemicals; DNA; DNA Damage; Biomarkers; Dietary Supplements
PubMed: 37573943
DOI: 10.1016/j.advnut.2023.08.004 -
Breast Cancer Research : BCR Jan 2020In patients with hormone receptor-positive breast cancer, differentiating between patients with a low and a high risk of recurrence is an ongoing challenge. In current...
BACKGROUND
In patients with hormone receptor-positive breast cancer, differentiating between patients with a low and a high risk of recurrence is an ongoing challenge. In current practice, prognostic clinical parameters are used for risk prediction. DNA methylation markers have been proven to be of additional prognostic value in several cancer types. Numerous prognostic DNA methylation markers for breast cancer have been published in the literature. However, to date, none of these markers are used in clinical practice.
METHODS
We conducted a systematic review of PubMed and EMBASE to assess the number and level of evidence of published DNA methylation markers for hormone receptor-positive breast cancer. To obtain an overview of the reporting quality of the included studies, all were scored according to the REMARK criteria that were established as reporting guidelines for prognostic biomarker studies.
RESULTS
A total of 74 studies were identified reporting on 87 different DNA methylation markers. Assessment of the REMARK criteria showed variation in reporting quality of the studies. Eighteen single markers and one marker panel were studied in multiple independent populations. Hypermethylation of the markers RASSF1, BRCA, PITX2, CDH1, RARB, PCDH10 and PGR, and the marker panel GSTP1, RASSF1 and RARB showed a statistically significant correlation with poor disease outcome that was confirmed in at least one other, independent study.
CONCLUSION
This systematic review provides an overview on published prognostic DNA methylation markers for hormone receptor-positive breast cancer and identifies eight markers that have been independently validated. Analysis of the reporting quality of included studies suggests that future research on this topic would benefit from standardised reporting guidelines.
Topics: Antigens, CD; BRCA1 Protein; Biomarkers, Tumor; Breast Neoplasms; Cadherins; DNA Methylation; Estrogen Receptor alpha; Female; Glutathione S-Transferase pi; Homeodomain Proteins; Humans; Intracellular Signaling Peptides and Proteins; Neoplasm Recurrence, Local; Nuclear Proteins; Prognosis; Protocadherins; Receptors, Progesterone; Receptors, Retinoic Acid; Transcription Factors; Tumor Suppressor Proteins; Homeobox Protein PITX2
PubMed: 32005275
DOI: 10.1186/s13058-020-1250-9 -
Journal of Oncology 2022Although the effects of methylation of the Ras association domain-containing protein 1 isoform A () gene in cell-free DNA on the outcomes of patients with different... (Review)
Review
BACKGROUND
Although the effects of methylation of the Ras association domain-containing protein 1 isoform A () gene in cell-free DNA on the outcomes of patients with different types of cancer have been reported, the results are inconsistent.
OBJECTIVE
: To explore the relationships between methylation in cell-free DNA and the outcomes of cancer patients.
METHODS
The PubMed, Embase, and Web of Science databases were searched for papers related to this topic on December 8, 2021. The retrieved articles were screened by two independent researchers, following which the methodological quality of the selected studies was evaluated using the Newcastle-Ottawa Scale. Additionally, hazard ratios were calculated, and publication bias of the studies was determined using Egger's test.
RESULTS
Nine relevant publications involving a combined total of 1254 patients with different types of cancer were included in this study. The combined results of the random effects models yielded a hazard ratio of 1.73 (95% confidence interval: 1.31, 2.29; < 0.001), which suggested there was a significant association between methylation and overall survival, and patients with an methylation status had a significantly increased risk of total death. Moreover, the Egger test result suggested there was no significant publication bias among the included studies.
CONCLUSIONS
The methylation of in cell-free DNA in cancer patients was observably associated with an increased risk of poor overall survival.
PubMed: 35528240
DOI: 10.1155/2022/3458420