scholarly journals The methylation level of TFAP2A is a potential diagnostic biomarker for retinoblastoma: an analytical validation study

PeerJ ◽  
2021 ◽  
Vol 9 ◽  
pp. e10830
Author(s):  
Qi Zeng ◽  
Sha Wang ◽  
Jia Tan ◽  
Lu Chen ◽  
Jinwei Wang
Keyword(s):  
Aqueous Humor ◽  
Circulating Tumor Dna ◽  
Retinal Diseases ◽  
Tissue Samples ◽  
Diagnostic Biomarkers ◽  
Normal Retina ◽  
Genome Wide ◽  
A Genome ◽  
Probe Set ◽  
Methylation Profiling

Tumor-derived circulating tumor DNA (ctDNA) has demonstrated its excellent potential for cancer diagnosis by DNA methylome; therefore, this study aimed to identify the retinoblastoma (RB) specific methylated CpG loci as the RB diagnostic biomarkers and design a methylation specific assay to detect these biomarker from aqueous humor of RB patients. Through a genome-wide methylation profiling of tissue samples from patients with RB, normal retina and other retinal diseases, we shortlisted two CpG loci were only methylated in RB but not in normal retina or other retinal diseases. Both of these two CpG loci were located in the genome of TFAP2A. Through the screening, a primer and probe set for the two CpG loci were tested in fully methylated standards and RB tissues with a significant differentiation of RB. Our results of this assay tested in aqueous humor from RB revealed an accuracy of 92.7% for RB diagnosis. These results suggested our assay targeting the TFAP2A ctDNA methylation can be utilized for RB diagnosis and cancer monitoring.

scholarly journals Epigenetic Mechanisms of the Aging Human Retina

2015 ◽  
Vol 9s2 ◽  
pp. JEN.S25513 ◽  
Author(s):  
Katie L. Pennington ◽  
Margaret M. Deangelis
Keyword(s):  
Gene Expression ◽  
Risk Factors ◽  
Environmental Risk ◽  
Environmental Risk Factors ◽  
Age Related Macular Degeneration ◽  
Retinal Diseases ◽  
Epigenetic Mechanisms ◽  
Tissue Samples ◽  
Age Related ◽  
Genome Wide

Degenerative retinal diseases, such as glaucoma, age-related macular degeneration, and diabetic retinopathy, have complex etiologies with environmental, genetic, and epigenetic contributions to disease pathology. Much effort has gone into elucidating both the genetic and the environmental risk factors for these retinal diseases. However, little is known about how these genetic and environmental risk factors bring about molecular changes that lead to pathology. Epigenetic mechanisms have received extensive attention of late for their promise of bridging the gap between environmental exposures and disease development via their influence on gene expression. Recent studies have identified epigenetic changes that associate with the incidence and/or progression of each of these retinal diseases. Therefore, these epigenetic modifications may be involved in the underlying pathological mechanisms leading to blindness. Further genome-wide epigenetic studies that incorporate well-characterized tissue samples, consider challenges similar to those relevant to gene expression studies, and combine the genome-wide epigenetic data with genome-wide genetic and expression data to identify additional potentially causative agents of disease are needed. Such studies will allow researchers to create much-needed therapeutics to prevent and/or intervene in disease progression. Improved therapeutics will greatly enhance the quality of life and reduce the burden of disease management for millions of patients living with these potentially blinding conditions.

scholarly journals Circular RNAs in Clear Cell Renal Cell Carcinoma: Their Microarray-Based Identification, Analytical Validation, and Potential Use in a Clinico-Genomic Model to Improve Prognostic Accuracy

Cancers ◽  
2019 ◽  
Vol 11 (10) ◽  
pp. 1473 ◽  
Author(s):  
Franz ◽  
Ralla ◽  
Weickmann ◽  
Jung ◽  
Rochow ◽  
...  
Keyword(s):  
Normal Tissue ◽  
Cox Regression ◽  
Clear Cell ◽  
Information Criteria ◽  
Circular Rnas ◽  
Cell Renal Cell Carcinoma ◽  
Tissue Samples ◽  
Cox Regression Analysis ◽  
Genome Wide ◽  
A Genome

Circular RNAs (circRNAs) may act as novel cancer biomarkers. However, a genome-wide evaluation of circRNAs in clear cell renal cell carcinoma (ccRCC) has yet to be conducted. Therefore, the objective of this study was to identify and validate circRNAs in ccRCC tissue with a focus to evaluate their potential as prognostic biomarkers. A genome-wide identification of circRNAs in total RNA extracted from ccRCC tissue samples was performed using microarray analysis. Three relevant differentially expressed circRNAs were selected (circEGLN3, circNOX4, and circRHOBTB3), their circular nature was experimentally confirmed, and their expression—along with that of their linear counterparts—was measured in 99 malignant and 85 adjacent normal tissue samples using specifically established RT-qPCR assays. The capacity of circRNAs to discriminate between malignant and adjacent normal tissue samples and their prognostic potential (with the endpoints cancer-specific, recurrence-free, and overall survival) after surgery were estimated by C-statistics, Kaplan-Meier method, univariate and multivariate Cox regression analysis, decision curve analysis, and Akaike and Bayesian information criteria. CircEGLN3 discriminated malignant from normal tissue with 97% accuracy. We generated a prognostic for the three endpoints by multivariate Cox regression analysis that included circEGLN3, circRHOBT3 and linRHOBTB3. The predictive outcome accuracy of the clinical models based on clinicopathological factors was improved in combination with this circRNA-based signature. Bootstrapping as well as Akaike and Bayesian information criteria confirmed the statistical significance and robustness of the combined models. Limitations of this study include its retrospective nature and the lack of external validation. The study demonstrated the promising potential of circRNAs as diagnostic and particularly prognostic biomarkers in ccRCC patients.

scholarly journals Dysregulation of alternative splicing is associated with the pathogenesis of ulcerative colitis

2021 ◽  
Vol 20 (1) ◽  
Author(s):  
Daowei Li ◽  
Yue Tan
Keyword(s):  
Ulcerative Colitis ◽  
Alternative Splicing ◽  
Tissue Samples ◽  
Therapeutic Implications ◽  
Aberrant Gene Expression ◽  
Genome Wide ◽  
Genomic Landscape ◽  
A Genome ◽  
Post Transcriptional Regulation ◽  
Aberrant Gene

Abstract Background Although numerous risk loci for ulcerative colitis (UC) have been identified in the human genome, the pathogenesis of UC remains unclear. Recently, multiple transcriptomic analyses have shown that aberrant gene expression in the colon tissues of UC patients is associated with disease progression. A pioneering study also demonstrated that altered post-transcriptional regulation is involved in the progression of UC. Here, we provide a genome-wide analysis of alternative splicing (AS) signatures in UC patients. We analyzed three datasets containing 74 tissue samples from UC patients and identified over 2000 significant AS events. Results Skipped exon and alternative first exon were the two most significantly altered AS events in UC patients. The immune response-related pathways were remarkably enriched in the UC-related AS events. Genes with significant AS events were more likely to be dysregulated at the expression level. Conclusions We present a genomic landscape of AS events in UC patients based on a combined analysis of two cohorts. Our results indicate that dysregulation of AS may have a pivotal role in determining the pathogenesis of UC. In addition, our study uncovers genes with potential therapeutic implications for UC treatment.

scholarly journals Analysis of the CDK4/6 Cell Cycle Pathway in Leiomyosarcomas as a Potential Target for Inhibition by Palbociclib

Sarcoma ◽  
2019 ◽  
Vol 2019 ◽  
pp. 1-10 ◽  
Author(s):  
Michael J. Böhm ◽  
Ralf Marienfeld ◽  
Daniela Jäger ◽  
Kevin Mellert ◽  
Adrian von Witzleben ◽  
...  
Keyword(s):  
Targeted Therapy ◽  
Cell Line ◽  
Tissue Samples ◽  
Protein Levels ◽  
Genomic Complexity ◽  
Genome Wide ◽  
A Genome ◽  
Genomic Aberrations ◽  
Cell Cycle Pathway

Leiomyosarcoma (LMS) is characterized by high genomic complexity, and to date, no specific targeted therapy is available. In a genome-wide approach, we profiled genomic aberrations in a small cohort of eight primary tumours, two relapses, and eight metastases across nine different patients. We identified CDK4 amplification as a recurrent alteration in 5 out of 18 samples (27.8%). It has been previously shown that the LMS cell line SK-LMS-1 has a defect in the p16 pathway and that this cell line can be inhibited by the CDK4 and CDK6 inhibitor palbociclib. For SK-LMS-1 we confirm and for SK-UT-1 we show that both LMS cell lines express CDK4 and that, in addition, strong CDK6 expression is seen in SK-LMS-1, whereas Rb was expressed in SK-LMS-1 but not in SK-UT-1. We confirm that inhibition of SK-LMS-1 with palbociclib led to a strong decrease in protein levels of Phospho-Rb (Ser780), a decreased cell proliferation, and G0/G1-phase arrest with decreased S/G2fractions. SK-UT-1 did not respond to palbociclib inhibition. To compare thesein vitrofindings with patient tissue samples, a p16, CDK4, CDK6, and p-Rb immunohistochemical staining assay of a large LMS cohort (n=99patients with 159 samples) was performed assigning a potential responder phenotype to each patient, which we identified in 29 out of 99 (29.3%) patients. Taken together, these data show that CDK4/6 inhibitors may offer a new option for targeted therapy in a subset of LMS patients.

scholarly journals Genome-Wide Perturbations of Alu Expression and Alu-Associated Post-Transcriptional Regulations Find a Uniqueness in Oligodendroglioma

2021 ◽  
Author(s):  
Taeyoung Hwang ◽  
Sojin Kim ◽  
Tamrin Chowdhury ◽  
Hyeon Jong Yu ◽  
Kyung-Min Kim ◽  
...  
Keyword(s):  
Brain Tumor ◽  
Regulatory Element ◽  
Circular Rna ◽  
Circular Rnas ◽  
Global Changes ◽  
Rna Seq ◽  
Tissue Samples ◽  
Genome Wide ◽  
A Genome

Abstract BackgroundAlu is a primate-specific repeat element in the human genome and has been increasingly appreciated as a regulatory element in many biological processes. But the role of Alu has not been studied comprehensively in brain tumor because an evolutionary perspective has been the subject of little research in brain tumor. We aim to investigate the relevance of Alu to the gliomagenesis.MethodsUsing a total of 41 pairs of neurotypicial brain tissue samples and samples of diverse gliomas, we performed strand-specific RNA-seq and analyzed two Alu-associated post-transcriptional regulations, A-to-I editing and circular RNAs, and Alu expression in a genome-wide way. ResultsWe found that while both A-to-I editing and circular RNA are decreased overall in gliomas, grade 2 oligodendrogliomas do not show this same pattern of global changes. Instead, in comparison with other gliomas, oligodendrogliomas showed a higher proportion of perturbed Alu RNA. Adenosine deaminase acting on RNA 2 (ADAR2) was down-regulated in gliomas other than grade 2 oligodendrogliomas, contributing to the observed Alu-associated perturbation. ConclusionsOur results demonstrate that Alu is associated with glioma development and grade 2 oligodendroglioma exhibits a unique pattern of Alu-associated post-transcriptional regulations, which provides an insight to gliomagenesis from the perspective of an evolutionary genetic element.

scholarly journals Genome wide methylation profiling of selected matched soft tissue sarcomas identifies methylation changes in metastatic and recurrent disease

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Ana Cristina Vargas ◽  
Lesley-Ann Gray ◽  
Christine L. White ◽  
Fiona M. Maclean ◽  
Peter Grimison ◽  
...  
Keyword(s):  
Soft Tissue ◽  
Human Tissue ◽  
Recurrent Disease ◽  
Clonal Evolution ◽  
Soft Tissue Sarcomas ◽  
Methylation Array ◽  
Tissue Samples ◽  
Genome Wide ◽  
Matched Samples ◽  
Methylation Profiling

AbstractIn this study we used the Illumina Infinium Methylation array to investigate in a cohort of matched archival human tissue samples (n = 32) from 14 individuals with soft tissue sarcomas if genome-wide methylation changes occur during metastatic and recurrent (Met/Rec) disease. A range of sarcoma types were selected for this study: leiomyosarcoma (LMS), myxofibrosarcoma (MFS), rhabdomyosarcoma (RMS) and synovial sarcoma (SS). We identified differential methylation in all Met/Rec matched samples, demonstrating that epigenomic differences develop during the clonal evolution of sarcomas. Differentially methylated regions and genes were detected, not been previously implicated in sarcoma progression, including at PTPRN2 and DAXX in LMS, WT1-AS and TNXB in SS, VENTX and NTRK3 in pleomorphic RMS and MEST and the C14MC / miR-379/miR-656 in MFS. Our overall findings indicate the presence of objective epigenetic differences across primary and Met/Rec human tissue samples not previously reported.

scholarly journals The DNA methylation landscape in cancer

2019 ◽  
Vol 63 (6) ◽  
pp. 797-811 ◽  
Author(s):  
Ksenia Skvortsova ◽  
Clare Stirzaker ◽  
Phillippa Taberlay
Keyword(s):  
Dna Methylation ◽  
Dna Hydroxymethylation ◽  
Disease States ◽  
Genome Wide ◽  
A Genome ◽  
Long Read ◽  
Profiling Techniques ◽  
Wide Scale ◽  
Improved Methods ◽  
Methylation Profiling

Abstract As one of the most abundant and well-studied epigenetic modifications, DNA methylation plays an essential role in normal development and cellular biology. Global alterations to the DNA methylation landscape contribute to alterations in the transcriptome and deregulation of cellular pathways. Indeed, improved methods to study DNA methylation patterning and dynamics at base pair resolution and across individual DNA molecules on a genome-wide scale has highlighted the scope of change to the DNA methylation landscape in disease states, particularly during tumorigenesis. More recently has been the development of DNA hydroxymethylation profiling techniques, which allows differentiation between 5mC and 5hmC profiles and provides further insights into DNA methylation dynamics and remodeling in tumorigenesis. In this review, we describe the distribution of DNA methylation and DNA hydroxymethylation in different genomic contexts, first in normal cells, and how this is altered in cancer. Finally, we discuss DNA methylation profiling technologies and the most recent advances in single-cell methods, bisulfite-free approaches and ultra-long read sequencing techniques.

scholarly journals Genome-wide DNA methylation profiling in anorexia nervosa discordant identical twins

2022 ◽  
Vol 12 (1) ◽  
Author(s):  
C. Iranzo-Tatay ◽  
D. Hervas-Marin ◽  
L. M. Rojo-Bofill ◽  
D. Garcia ◽  
F. J. Vaz-Leal ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Anorexia Nervosa ◽  
Whole Blood ◽  
Monozygotic Twin ◽  
Psychological Traits ◽  
Metabolic Traits ◽  
Genome Wide ◽  
A Genome ◽  
Dna Methylation Profiling ◽  
Methylation Profiling

AbstractUp until now, no study has looked specifically at epigenomic landscapes throughout twin samples, discordant for Anorexia nervosa (AN). Our goal was to find evidence to confirm the hypothesis that epigenetic variations play a key role in the aetiology of AN. In this study, we quantified genome-wide patterns of DNA methylation using the Infinium Human DNA Methylation EPIC BeadChip array (“850 K”) in DNA samples isolated from whole blood collected from a group of 7 monozygotic twin pairs discordant for AN. Results were then validated performing a genome-wide DNA methylation profiling using DNA extracted from whole blood of a group of non-family-related AN patients and a group of healthy controls. Our first analysis using the twin sample revealed 9 CpGs associated to a gene. The validation analysis showed two statistically significant CpGs with the rank regression method related to two genes associated to metabolic traits, PPP2R2C and CHST1. When doing beta regression, 6 of them showed statistically significant differences, including 3 CpGs associated to genes JAM3, UBAP2L and SYNJ2. Finally, the overall pattern of results shows genetic links to phenotypes which the literature has constantly related to AN, including metabolic and psychological traits. The genes PPP2R2C and CHST1 have both been linked to the metabolic traits type 2 diabetes through GWAS studies. The genes UBAP2L and SYNJ2 have been related to other psychiatric comorbidity.

Abstract 4403: Significant Single Nucleotide Polymorphism Associated with Atrial Fibrillation Located on Chromosome 4q25 in a Whole Genome Association Study and Association with Left Atrial Gene Expression

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
Mina K Chung ◽  
David R Van Wagoner ◽  
Jonathan D Smith ◽  
Robert C Wirka ◽  
Eric J Topol ◽  
...  
Keyword(s):  
Atrial Fibrillation ◽  
Association Study ◽  
Left Atrial ◽  
Additive Model ◽  
P Value ◽  
Q Value ◽  
Tissue Samples ◽  
Genome Wide ◽  
A Genome ◽  
Genome Wide Significance

Introduction: Heritability studies of atrial fibrillation (AF) suggest a complex genetic basis for common AF. Recently a locus on chromosome 4q25 was associated with AF in a genome-wide association study (GWAS), but the mechanism by which this locus is associated with AF is unknown. Methods: To identify genetic variations associated with AF, we performed an analysis of AF as a secondary phenotype from a case-control GWAS of myocardial infarction. 210,178 autosomal SNPs of high quality were genotyped in 138 AF cases and 546 controls. Stratified score tests of the trend/additive model and general genotypic model were performed for each SNP. Genomic control and multidimensional scaling were used to control and assess population stratification. The SNP meeting genome-wide significance was genotyped in 46 left atrial appendage tissue samples for which we obtained expression levels for 22,184 transcripts. Cis expression traits within 1 megabase of the top SNP were tested for association with the SNP genotypes. Results: One SNP (rs4611994) met our per-SNP genome-wide significance thresholds (both a conservative Bonferroni threshold or a more liberal FDR-based threshold) for association with AF, which was in perfect linkage disequilibrium with the locus on chromosome 4q25 found in the deCODE genetics AF study (r 2 with SNP rs2200733=1.0). This SNP yielded an AF odds ratio of 2.28 under the additive model, with a p-value using genomic control/general genotype model of 5.0E-08, and a minor allele frequency 0.13 in controls and 0.25 in AF cases, and a genome-wide p-value of 0.046 by permutation analysis. In the 46 left atrial tissue samples, cis analysis demonstrated significant association between rs4611994 genotype and expression of LRIT3 (Leucine-rich repeat, immunoglobulin-like domain and transmembrane domain-containing protein 3) with q-value 2.22E-03 and the C isoform of PITX2 with q-value 7.50E-03. Conclusions: Our GWAS for common AF has replicated the AF-associated locus on chromosome 4q25. The genotype at this locus was correlated with cis regulation of the LRIT3 and PITX2C transcripts, suggesting these genes as candidates for mechanistic studies.

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