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Journal of Cancer Research and Clinical... Jan 2024Accurate and non-invasive estimation of MGMT promoter methylation status in glioblastoma (GBM) patients is of paramount clinical importance, as it is a predictive... (Review)
Review
BACKGROUND
Accurate and non-invasive estimation of MGMT promoter methylation status in glioblastoma (GBM) patients is of paramount clinical importance, as it is a predictive biomarker associated with improved overall survival (OS). In response to the clinical need, recent studies have focused on the development of non-invasive artificial intelligence (AI)-based methods for MGMT estimation. In this systematic review, we not only delve into the technical aspects of these AI-driven MGMT estimation methods but also emphasize their profound clinical implications. Specifically, we explore the potential impact of accurate non-invasive MGMT estimation on GBM patient care and treatment decisions.
METHODS
Employing a PRISMA search strategy, we identified 33 relevant studies from reputable databases, including PubMed, ScienceDirect, Google Scholar, and IEEE Explore. These studies were comprehensively assessed using 21 diverse attributes, encompassing factors such as types of imaging modalities, machine learning (ML) methods, and cohort sizes, with clear rationales for attribute scoring. Subsequently, we ranked these studies and established a cutoff value to categorize them into low-bias and high-bias groups.
RESULTS
By analyzing the 'cumulative plot of mean score' and the 'frequency plot curve' of the studies, we determined a cutoff value of 6.00. A higher mean score indicated a lower risk of bias, with studies scoring above the cutoff mark categorized as low-bias (73%), while 27% fell into the high-bias category.
CONCLUSION
Our findings underscore the immense potential of AI-based machine learning (ML) and deep learning (DL) methods in non-invasively determining MGMT promoter methylation status. Importantly, the clinical significance of these AI-driven advancements lies in their capacity to transform GBM patient care by providing accurate and timely information for treatment decisions. However, the translation of these technical advancements into clinical practice presents challenges, including the need for large multi-institutional cohorts and the integration of diverse data types. Addressing these challenges will be critical in realizing the full potential of AI in improving the reliability and accessibility of MGMT estimation while lowering the risk of bias in clinical decision-making.
Topics: Humans; Glioblastoma; Artificial Intelligence; Reproducibility of Results; DNA Methylation; Brain Neoplasms; DNA Modification Methylases; DNA Repair Enzymes; DNA; Tumor Suppressor Proteins
PubMed: 38291266
DOI: 10.1007/s00432-023-05566-5 -
Bioscience Reports Mar 2020O6-methylguanine-DNA methyltransferase (MGMT) is a specific DNA damage reversal repair protein. The influence of MGMT status on alkylating agent sensitivity in patients... (Meta-Analysis)
Meta-Analysis
BACKGROUND
O6-methylguanine-DNA methyltransferase (MGMT) is a specific DNA damage reversal repair protein. The influence of MGMT status on alkylating agent sensitivity in patients with neuroendocrine neoplasms (NENs) is controversial. We conducted a meta-analysis to assess the influence of MGMT status on the therapeutic sensitivity of alkylating agents in patients with NENs.
METHODS
We searched PubMed, EmBase, and Cochrane library public databases through 3 July 2019. The objective response rate (ORR) was the outcome data of interest. Subgroup analysis was performed according based on MGMT methylation and expression of MGMT protein.
RESULTS
Eleven studies were included in the meta-analysis. The proportion of patients with NENs that achieved an ORR after alkylating agent treatment was higher in the MGMT-deficient group than the non-deficient group (OR: 5.00; 95% CI: 3.04-8.22; P < 0.001; I2: 3%). Similar results were noted in the MGMT methylation and MGMT protein expression subgroups.
CONCLUSION
Patients with NENs and MGMT methylation or low protein expression had a higher ORR proportion than patients without MGMT methylation or high protein expression. The MGMT status can be used as a biological indicator of the response to alkylating agent treatment in patients with NENs.
Topics: Antineoplastic Agents, Alkylating; DNA Methylation; DNA Modification Methylases; DNA Repair Enzymes; Humans; Neuroendocrine Tumors; Promoter Regions, Genetic; Treatment Outcome; Tumor Suppressor Proteins
PubMed: 32141507
DOI: 10.1042/BSR20194127 -
Medicine Nov 2020The results of published articles on the relationship between the Val158Met polymorphism in the (Catechol-O-methyltransferase) COMT gene and the susceptibility of... (Meta-Analysis)
Meta-Analysis
BACKGROUND
The results of published articles on the relationship between the Val158Met polymorphism in the (Catechol-O-methyltransferase) COMT gene and the susceptibility of attention-deficit hyperactive disorder (ADHD) are controversial. We conducted an updated meta-analysis of case-control studies to assess the relationship between Val158Met polymorphism in COMT gene and ADHD susceptibility.
METHODS
A comprehensive literature search was conducted to identify all the case-control studies on the relationship between the COMT gene Val158Met polymorphism and ADHD susceptibility. According to the heterogeneity test results among studies evaluated with I, the fixed effect model or random effect model was selected as the pooling method. Meta-regression as well as sensitive analysis were used to explore possible causes of between-study heterogeneity. The funnel plot and Harbord test were used to estimate publication bias.
RESULTS
Finally, seventeen studies that met the inclusion criteria were included. The Val158Met genotype distributions of COMT gene in controls were in Hardy-Weinberg equilibrium in all studies. In general, there was no significant association between the COMT gene Val158Met polymorphism and ADHD susceptibility in dominant, recessive, and codominant models. The recessive genetic model (I = 60.8%) showed strong heterogeneity among studies, and still no significant association was found after sensitivity analysis. Subgroup analysis stratified by ethnicity (Asian and Caucasian) also showed that there was no significant association in the above-mentioned three models.
CONCLUSIONS
This updated meta-analysis indicated that the Val158Met polymorphism in the COMT gene may not be related to the risk of ADHD. Further researches are needed to confirm these results.
Topics: Attention Deficit Disorder with Hyperactivity; Catechol O-Methyltransferase; Genetic Predisposition to Disease; Genotype; Humans; Polymorphism, Single Nucleotide
PubMed: 33235119
DOI: 10.1097/MD.0000000000023400 -
PloS One 2022Analytic approaches to clinical validation of results from preclinical models are important in assessment of their relevance to human disease. This systematic review...
INTRODUCTION
Analytic approaches to clinical validation of results from preclinical models are important in assessment of their relevance to human disease. This systematic review examined consistency in reporting of glioblastoma cohorts from The Cancer Genome Atlas (TCGA) or Chinese Glioma Genome Atlas (CGGA) and assessed whether studies included patient characteristics in their survival analyses.
METHODS
We searched Embase and Medline on 02Feb21 for studies using preclinical models of glioblastoma published after Jan2008 that used data from TCGA or CGGA to validate the association between at least one molecular marker and overall survival in adult patients with glioblastoma. Main data items included cohort characteristics, statistical significance of the survival analysis, and model covariates.
RESULTS
There were 58 eligible studies from 1,751 non-duplicate records investigating 126 individual molecular markers. In 14 studies published between 2017 and 2020 using TCGA RNA microarray data that should have the same cohort, the median number of patients was 464.5 (interquartile range 220.5-525). Of the 15 molecular markers that underwent more than one univariable or multivariable survival analyses, five had discrepancies between studies. Covariates used in the 17 studies that used multivariable survival analyses were age (76.5%), pre-operative functional status (35.3%), sex (29.4%) MGMT promoter methylation (29.4%), radiotherapy (23.5%), chemotherapy (17.6%), IDH mutation (17.6%) and extent of resection (5.9%).
CONCLUSION
Preclinical glioblastoma studies that used TCGA for validation did not provide sufficient information about their cohort selection and there were inconsistent results. Transparency in reporting and the use of analytic approaches that adjust for clinical variables can improve the reproducibility between studies.
Topics: Adult; Brain Neoplasms; DNA Methylation; DNA Modification Methylases; DNA Repair Enzymes; Glioblastoma; Glioma; Humans; Prognosis; Reproducibility of Results
PubMed: 35231064
DOI: 10.1371/journal.pone.0264740 -
BMC Genomics Dec 2022Modern human brains and skull shapes differ from other hominids. Brain growth disorders as micro- (ASPM, MCPH1) and macrocephaly (NFIX, GLI3) have been highlighted as...
BACKGROUND
Modern human brains and skull shapes differ from other hominids. Brain growth disorders as micro- (ASPM, MCPH1) and macrocephaly (NFIX, GLI3) have been highlighted as relevant for the evolution in humans due to the impact in early brain development. Genes associated with macrocephaly have been reported to cause this change, for example NSD1 which causes Sotos syndrome.
RESULTS
In this study we performed a systematic literature review, located the reported variants associated to Sotos syndrome along the gene domains, compared the sequences with close primates, calculated their similarity, Ka/Ks ratios, nucleotide diversity and selection, and analyzed the sequence and structural conservation with distant primates. We aimed to understand if NSD1 in humans differs from other primates since the evolution of NSD1 has not been analyzed in primates, nor if the localization of the mutations is limited to humans. Our study found that most variations causing Sotos syndrome are in exon 19, 22 and 10. In the primate comparison we did not detect Ka/Ks ratios > 1, but a high nucleotide diversity with non-synonymous variations in exons 10, 5, 9, 11 and 23, and sites under episodic selection in exon 5 and 23, and human, macaque/colobus/tarsier/galago and tarsier/lemur/colobus. Most of the domains are conserved in distant primates with a particular progressive development from a simple PWWP1 in O. garnetti to a complex structure in Human.
CONCLUSION
NSD1 is a chromatin modifier that suggests that the selection could influence brain development during modern human evolution and is not present in other primates; however, nowadays the nucleotide diversity is associated with Sotos syndrome.
Topics: Humans; Animals; Sotos Syndrome; Histone Methyltransferases; Histone-Lysine N-Methyltransferase; Tarsiidae; Colobus; Nuclear Proteins; Mutation; Exons; Hominidae; Megalencephaly; Nucleotides; Cytoskeletal Proteins; Cell Cycle Proteins
PubMed: 36550402
DOI: 10.1186/s12864-022-09071-w -
Pharmacogenomics Apr 2016Thiopurine S-methyltransferase (TPMT) testing is used in patients receiving thiopurines to identify enzyme deficiencies and risk for adverse drug reactions. It is...
AIM
Thiopurine S-methyltransferase (TPMT) testing is used in patients receiving thiopurines to identify enzyme deficiencies and risk for adverse drug reactions. It is uncertain whether genotyping is superior to phenotyping. The objectives were to conduct a systematic review of TPMT-test performance studies.
MATERIALS & METHODS
Electronic and grey literature sources were searched for studies reporting test performance compared with a reference standard. Sixty-six eligible studies were appraised for quality.
RESULTS
Thirty phenotype-genotype and six phenotype-phenotype comparisons were of high quality. The calculated sensitivity and specificity for genotyping to identify a homozygous mutation ranged from 0.0-100.0% and from 97.8-100.0%, respectively.
CONCLUSION
Clinical decision-makers require high-quality evidence of clinical validity and clinical utility of TPMT genotyping to ensure appropriate use in patients.
Topics: Adolescent; Adult; Drug-Related Side Effects and Adverse Reactions; Female; Genetic Testing; Genotype; Humans; Male; Methyltransferases; Mutation; Phenotype; Sensitivity and Specificity
PubMed: 27020704
DOI: 10.2217/pgs.16.12 -
Genetics and Molecular Research : GMR Dec 2015The objective of this study was to perform a systematic review of the correlations between the single nucleotide polymorphism rs4680 in the catechol-O-methyltransferase... (Meta-Analysis)
Meta-Analysis
The objective of this study was to perform a systematic review of the correlations between the single nucleotide polymorphism rs4680 in the catechol-O-methyltransferase (COMT) gene and susceptibility to ovarian cancer. A computer search was carried out for relevant case-control studies published between January 2000 to January 2014 in databases such as Ovid, EBSCO, PubMed, CNKI, CBMDISC, VIP, and WanFang Data. The literature was screened based on inclusion and exclusion criteria. A meta-analysis was performed by calculating the combined odds ratios (OR) and 95% confidence intervals (CI) using the RevMan 5.0. A total of 7 case-control studies were selected, which included 1439 cases and 2927 control subjects. Meta-analysis showed that the rs4680 polymorphism was not associated with ovarian cancer [GG vs (GA+AA): OR = 1.02, 95%CI = 0.88-1.19; G vs A allele: OR = 1.0, 95%CI = 0.90-1.11]. We, therefore, conclude that the COMT rs4680 polymorphism is not associated with susceptibility to ovarian cancer.
Topics: Alleles; Case-Control Studies; Catechol O-Methyltransferase; Female; Genetic Association Studies; Genetic Predisposition to Disease; Genotype; Humans; Odds Ratio; Ovarian Neoplasms; Polymorphism, Single Nucleotide; Publication Bias
PubMed: 26681027
DOI: 10.4238/2015.December.14.8 -
European Radiology Feb 2024To evaluate the methodological quality and diagnostic accuracy of MRI-based radiomic studies predicting O6-methylguanine-DNA methyltransferase (MGMT) promoter...
OBJECTIVES
To evaluate the methodological quality and diagnostic accuracy of MRI-based radiomic studies predicting O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation status in gliomas.
METHODS
PubMed Medline, EMBASE, and Web of Science were searched to identify MRI-based radiomic studies on MGMT methylation in gliomas published until December 31, 2022. Three raters evaluated the study methodological quality with Radiomics Quality Score (RQS, 16 components) and Transparent Reporting of a Multivariable Prediction Model for Individual Prognosis Or Diagnosis (TRIPOD, 22 items) scales. Risk of bias and applicability concerns were assessed with QUADAS-2 tool. A meta-analysis was performed to estimate the pooled area under the curve (AUC) and to assess inter-study heterogeneity.
RESULTS
We included 26 studies, published from 2016. The median RQS total score was 8 out of 36 (22%, range 8-44%). Thirteen studies performed external validation. All studies reported AUC or accuracy, but only 4 (15%) performed calibration and decision curve analysis. No studies performed phantom analysis, cost-effectiveness analysis, and prospective validation. The overall TRIPOD adherence score was between 50% and 70% in 16 studies and below 50% in 10 studies. The pooled AUC was 0.78 (95% CI, 0.73-0.83, I = 94.1%) with a high inter-study heterogeneity. Studies with external validation and including only WHO-grade IV gliomas had significantly lower AUC values (0.65; 95% CI, 0.57-0.73, p < 0.01).
CONCLUSIONS
Study RQS and adherence to TRIPOD guidelines was generally low. Radiomic prediction of MGMT methylation status showed great heterogeneity of results and lower performances in grade IV gliomas, which hinders its current implementation in clinical practice.
CLINICAL RELEVANCE STATEMENT
MGMT promoter methylation status appears to be variably correlated with MRI radiomic features; radiomic models are not sufficiently robust to be integrated into clinical practice to accurately predict MGMT promoter methylation status in patients with glioma before surgery.
KEY POINTS
• Adherence to the indications of TRIPOD guidelines was generally low, as was RQS total score. • MGMT promoter methylation status prediction with MRI radiomic features provided heterogeneous diagnostic accuracy results across studies. • Studies that included grade IV glioma only and performed external validation had significantly lower diagnostic accuracy than others.
PubMed: 38308012
DOI: 10.1007/s00330-024-10594-x -
Frontiers in Endocrinology 2021The CDK5 regulatory subunit-associated protein 1-like 1 () contributes to islet β-cell function and insulin secretion by inhibiting the activation of CDK5. The current... (Meta-Analysis)
Meta-Analysis
OBJECTIVES
The CDK5 regulatory subunit-associated protein 1-like 1 () contributes to islet β-cell function and insulin secretion by inhibiting the activation of CDK5. The current studies on the relationship between polymorphisms rs7756992 A>G and rs7754840 C>G and the risk of gestational diabetes mellitus (GDM) have drawn contradictory conclusions.
MATERIALS AND METHODS
A meta-analysis with a fixed- or random-effects model was conducted to estimate the correlation between studied polymorphisms and GDM risk with the summary odds ratio (OR) and 95% confidence interval (CI). In addition, trial sequential analysis (TSA) and false-positive report probability (FPRP) analysis were performed to confirm the study findings.
RESULTS
A total of 13,306 subjects were included in the present study. Meta-analysis results showed that the variant heterozygous and homozygous genotypes of the two polymorphisms were associated with increased GDM risk in comparison with the wild-type AA genotype (AG AA: OR = 1.23, 95% CI = 1.08, 1.41, = 0.002; GG AA: OR = 1.47, 95% CI = 1.05, 2.05, = 0.024 for rs7756992; and CG GG: OR = 1.36, 95% CI = 1.13, 1.65, = 0.002; CC GG: OR = 1.76, 95% CI = 1.37, 2.26, < 0.001 for rs7754840). The TSA confirmed a significant association between rs7754840 and the susceptibility to GDM because the cumulative Z-curve crossed both the conventional cutoff value and the TSA boundaries under the heterozygote and homozygote models.
CONCLUSIONS
This study supported the finding that rs7756992 and rs7754840 are associated with susceptibility to GDM. However, further functional studies are warranted to clarify the mechanism.
Topics: Case-Control Studies; Cyclin-Dependent Kinase 5; Diabetes, Gestational; Female; Genetic Predisposition to Disease; Genome-Wide Association Study; Humans; Polymorphism, Single Nucleotide; Pregnancy; Risk Factors; tRNA Methyltransferases
PubMed: 34721291
DOI: 10.3389/fendo.2021.722674 -
The Cochrane Database of Systematic... Mar 2021Glioblastoma is an aggressive form of brain cancer. Approximately five in 100 people with glioblastoma survive for five years past diagnosis. Glioblastomas that have a... (Meta-Analysis)
Meta-Analysis
Prognostic value of test(s) for O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation for predicting overall survival in people with glioblastoma treated with temozolomide.
BACKGROUND
Glioblastoma is an aggressive form of brain cancer. Approximately five in 100 people with glioblastoma survive for five years past diagnosis. Glioblastomas that have a particular modification to their DNA (called methylation) in a particular region (the O-methylguanine-DNA methyltransferase (MGMT) promoter) respond better to treatment with chemotherapy using a drug called temozolomide.
OBJECTIVES
To determine which method for assessing MGMT methylation status best predicts overall survival in people diagnosed with glioblastoma who are treated with temozolomide.
SEARCH METHODS
We searched MEDLINE, Embase, BIOSIS, Web of Science Conference Proceedings Citation Index to December 2018, and examined reference lists. For economic evaluation studies, we additionally searched NHS Economic Evaluation Database (EED) up to December 2014.
SELECTION CRITERIA
Eligible studies were longitudinal (cohort) studies of adults with diagnosed glioblastoma treated with temozolomide with/without radiotherapy/surgery. Studies had to have related MGMT status in tumour tissue (assessed by one or more method) with overall survival and presented results as hazard ratios or with sufficient information (e.g. Kaplan-Meier curves) for us to estimate hazard ratios. We focused mainly on studies comparing two or more methods, and listed brief details of articles that examined a single method of measuring MGMT promoter methylation. We also sought economic evaluations conducted alongside trials, modelling studies and cost analysis.
DATA COLLECTION AND ANALYSIS
Two review authors independently undertook all steps of the identification and data extraction process for multiple-method studies. We assessed risk of bias and applicability using our own modified and extended version of the QUality In Prognosis Studies (QUIPS) tool. We compared different techniques, exact promoter regions (5'-cytosine-phosphate-guanine-3' (CpG) sites) and thresholds for interpretation within studies by examining hazard ratios. We performed meta-analyses for comparisons of the three most commonly examined methods (immunohistochemistry (IHC), methylation-specific polymerase chain reaction (MSP) and pyrosequencing (PSQ)), with ratios of hazard ratios (RHR), using an imputed value of the correlation between results based on the same individuals.
MAIN RESULTS
We included 32 independent cohorts involving 3474 people that compared two or more methods. We found evidence that MSP (CpG sites 76 to 80 and 84 to 87) is more prognostic than IHC for MGMT protein at varying thresholds (RHR 1.31, 95% confidence interval (CI) 1.01 to 1.71). We also found evidence that PSQ is more prognostic than IHC for MGMT protein at various thresholds (RHR 1.36, 95% CI 1.01 to 1.84). The data suggest that PSQ (mainly at CpG sites 74 to 78, using various thresholds) is slightly more prognostic than MSP at sites 76 to 80 and 84 to 87 (RHR 1.14, 95% CI 0.87 to 1.48). Many variants of PSQ have been compared, although we did not see any strong and consistent messages from the results. Targeting multiple CpG sites is likely to be more prognostic than targeting just one. In addition, we identified and summarised 190 articles describing a single method for measuring MGMT promoter methylation status.
AUTHORS' CONCLUSIONS
PSQ and MSP appear more prognostic for overall survival than IHC. Strong evidence is not available to draw conclusions with confidence about the best CpG sites or thresholds for quantitative methods. MSP has been studied mainly for CpG sites 76 to 80 and 84 to 87 and PSQ at CpG sites ranging from 72 to 95. A threshold of 9% for CpG sites 74 to 78 performed better than higher thresholds of 28% or 29% in two of three good-quality studies making such comparisons.
Topics: Adult; Antineoplastic Agents, Alkylating; Bias; Brain Neoplasms; Cohort Studies; CpG Islands; DNA Methylation; DNA Modification Methylases; DNA Repair Enzymes; Glioblastoma; High-Throughput Nucleotide Sequencing; Humans; Immunohistochemistry; Polymerase Chain Reaction; Predictive Value of Tests; Prognosis; Promoter Regions, Genetic; Temozolomide; Tumor Suppressor Proteins
PubMed: 33710615
DOI: 10.1002/14651858.CD013316.pub2