DNA-methylation in C1R is a prognostic biomarker for acute myeloid leukemia.
Ontology highlight
ABSTRACT:
SUBMITTER: Bozic T
PROVIDER: S-EPMC4632269 | biostudies-literature | 2015
REPOSITORIES: biostudies-literature
Publications
DNA-methylation in C1R is a prognostic biomarker for acute myeloid leukemia.
Božić Tanja T Lin Qiong Q Frobel Joana J Wilop Stefan S Hoffmann Melanie M Müller-Tidow Carsten C Brümmendorf Tim H TH Jost Edgar E Wagner Wolfgang W
Clinical epigenetics 20151104
<h4>Background</h4>Epigenetic aberrations play a central role in the pathophysiology of acute myeloid leukemia (AML). It has been shown that molecular signatures based on DNA-methylation (DNAm) patterns can be used for classification of the disease. In this study, we followed the hypothesis that DNAm at a single CpG site might support risk stratification in AML.<h4>Findings</h4>Using DNAm profiles of 194 patients from The Cancer Genome Atlas (TCGA), we identified a CpG site in complement compone ...[more]
Similar Datasets
Project description:BackgroundAcute myeloid leukemia (AML) is a heterogeneous clonal disease that prevents normal myeloid differentiation with its common features. Its incidence increases with age and has a poor prognosis. Studies have shown that DNA methylation and abnormal gene expression are closely related to AML.MethodsThe methylation array data and mRNA array data are from the Gene Expression Omnibus (GEO) database. Through the GEO data, we identified differential genes from tumors and normal samples. Then we performed Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO) analyses on these differential genes. Protein-protein interaction (PPI) network construction and module analysis were performed to screen the highest-scoring modules. Next, we used SurvExpress software to analyze the genes in the highest-scoring module and selected potential prognostic genes by univariate and multivariate Cox analysis. Finally, the three genes screened by SurvExpress software were analyzed using the methylation analysis site MethSurv to explore AML associated methylation biomarkers.ResultsWe found three genes that can be used as independent prognostic factors for AML. These three genes are the low expression/methylation genes ATP11A and ITGAM, and the high expression/low methylation gene ZNRF2.ConclusionsIn this study, we performed a comprehensive analysis of DNA methylation and gene expression to identify key epigenetic genes in AML.
| S-EPMC6989983 | biostudies-literature
Project description:Acute myeloid leukemia (AML) is a threatening hematological malignant disease in which new successful approaches in therapy are needed. Cyclin-dependent kinase 6 (CDK6), a regulatory enzyme of the cell cycle that plays an important role in leukemogenesis and the maintenance of leukemia stem cells (LSC), has the potential to predict the prognosis of AML. By analyzing public databases, we observed that the messenger RNA (mRNA) levels of CDK6 were significantly overexpressed in AML cell lines and non-acute promyelocytic leukemia (non-APL) AML patients when compared to healthy donors. Furthermore, CDK6 expression was significantly reduced in AML patients who achieved complete remission (CR) compared to that at the time of diagnosis in our validated cohort. The expression of CDK6 was tightly correlated with peripheral blood blasts, French-American-British (FAB) subtypes, CCAAT-enhancer-binding protein α (CEBPA) mutation, and chromosomal abnormalities of t(8;21). However, the clinical significance and effects of CDK6 expression on the prognosis of non-APL AML patients remain uncertain. We found that CDK6 expression was inversely correlated with overall survival (OS) among non-APL AML patients using the Kaplan-Meier analysis. CDK6 was also found to be positively associated with genes identified to contribute to the development of leukemia, including CCND2, DNMT3B, SOX4, and IKZF2, as well as being negatively associated with anticancer microRNAs, including miR-187, miR-9, miR-582, miR708, and miR-362. In summary, our study revealed that CDK6 might be a potential diagnostic and prognostic biomarker in non-APL AML patients.
| S-EPMC7882723 | biostudies-literature
Project description:Acute myeloid leukemia (AML) is the type of hematologic neoplasm most common in adults. Glucocorticoid-induced gene TSC22D3 regulates cell proliferation through its function as a transcription factor. However, there is no consensus on the prognostic and immunoregulatory significance of TSC22D3 in AML. In the present study, we evaluated the correlation between TSC22D3 expression, immunoinfiltration, and prognostic significance in AML. Knockdown of TSC22D3 significantly attenuated the proliferation of Hel cells and increased sensitivity to cytarabine (Ara-c) drugs. Furthermore, TSC22D3 reduced the release of interleukin-1β (IL-1β) by inhibiting the NF-κB/NLRP3 signaling pathway, thereby inhibiting macrophage polarization to M1 subtype, and attenuating the pro-inflammatory tumor microenvironment. In conclusion, this study identified TSC22D3 as an immune-related prognostic biomarker for AML patients and suggested that therapeutic targeting of TSC22D3 may be a potential treatment option for AML through tumor immune escape.
| S-EPMC10415931 | biostudies-literature
Project description:BackgroundMultiple studies have reported the prognostic impact of DNA methylation changes in acute myeloid leukemia (AML). However, these epigenetic markers have not been thoroughly validated and therefore are still not considered in clinical practice. Hence, we aimed to independently verify results of selected studies describing the relationship between DNA methylation of specific genes and their prognostic potential in predicting overall survival (OS) and event-free survival (EFS).ResultsFourteen studies (published 2011-2019) comprising of 27 genes were subjected to validation by a custom NGS-based sequencing panel in 178 newly diagnosed non-M3 AML patients treated by 3 + 7 induction regimen. The results were considered as successfully validated, if both the log-rank test and multivariate Cox regression analysis had a p-value ≤ 0.05. The predictive role of DNA methylation was confirmed for three studies comprising of four genes: CEBPA (OS: p = 0.02; EFS: p = 0.03), PBX3 (EFS: p = 0.01), LZTS2 (OS: p = 0.05; EFS: p = 0.0003), and NR6A1 (OS: p = 0.004; EFS: p = 0.0003). For all of these genes, higher methylation was an indicator of longer survival. Concurrent higher methylation of both LZTS2 and NR6A1 was highly significant for survival in cytogenetically normal (CN) AML group (OS: p < 0.0001; EFS: p < 0.0001) as well as for the whole AML cohort (OS: p = 0.01; EFS < 0.0001). In contrast, for two studies reporting the poor prognostic effect of higher GPX3 and DLX4 methylation, we found the exact opposite, again linking higher GPX3 (OS: p = 0.006; EFS: p < 0.0001) and DLX4 (OS: p = 0.03; EFS = 0.03) methylation to a favorable treatment outcome. Individual gene significance levels refer to the outcomes of multivariate Cox regression analysis.ConclusionsOut of twenty-seven genes subjected to DNA methylation validation, a prognostic role was observed for six genes. Therefore, independent validation studies are necessary to reveal truly prognostic DNA methylation changes and to enable the introduction of these promising epigenetic markers into clinical practice.
| S-EPMC8832751 | biostudies-literature
Project description:We investigated genome-wide DNA methylation patterns in 64 pediatric patients with acute myeloid leukemia (AML). Based on unsupervised clustering with the 567 most variably methylated cytosine guanine dinucleotide (CpG) sites, patients were categorized into 4 clusters associated with genetic alterations. Clusters 1 and 3 were characterized by the presence of known favorable prognostic factors, such as RUNX1-RUNX1T1 fusion and KMT2A rearrangement with low MECOM expression, and biallelic CEBPA mutations (all 8 patients), respectively. Clusters 2 and 4 comprised patients exhibiting molecular features associated with adverse outcomes, namely internal tandem duplication of FLT3 (FLT3-ITD), partial tandem duplication of KMT2A, and high PRDM16 expression. Depending on the methylation values of the 1243 CpG sites that were significantly different between FLT3-ITD+ and FLT3-ITD- AML, patients were categorized into 3 clusters: A, B, and C. The STAT5-binding motif was most frequently found close to the 1243 CpG sites. All 8 patients with FLT3-ITD in cluster A harbored high PRDM16 expression and experienced adverse events, whereas only 1 of 7 patients with FLT3-ITD in the other clusters experienced adverse events. PRDM16 expression levels were also related to DNA methylation patterns, which were drastically changed at the cutoff value of PRDM16/ABL1 = 0.10. The assay for transposase-accessible chromatin sequencing of AMLs supported enhanced chromatin accessibility around genomic regions, such as HOXB cluster genes, SCHIP1, and PRDM16, which were associated with DNA methylation changes in AMLs with FLT3-ITD and high PRDM16 expression. Our results suggest that DNA methylation levels at specific CpG sites are useful to support genetic alterations and gene expression patterns of patients with pediatric AML.
| S-EPMC9198913 | biostudies-literature
Project description:Integration of orthogonal data could provide new opportunities to pinpoint the underlying molecular mechanisms of hematologic disorders. Using a novel gene network approach, we integrated DNA methylation data from The Cancer Genome Atlas (n = 194 cases) with the corresponding gene expression profile. Our integrated gene network analysis classified AML patients into low-, intermediate-, and high-risk groups. The identified high-risk group had significantly shorter overall survival compared to the low-risk group (p-value ≤10-11). Specifically, our approach identified a particular subgroup of nine high-risk AML cases that died within 2 years after diagnosis. These high-risk cases otherwise would be incorrectly classified as intermediate-risk solely based on cytogenetics, mutation profiles, and common molecular characteristics of AML. We confirmed the prognostic value of our integrative gene network approach using two independent datasets, as well as through comparison with European LeukemiaNet and LSC17 criteria. Our approach could be useful in the prognostication of a subset of borderline AML cases. These cases would not be classified into appropriate risk groups by other approaches that use gene expression, but not DNA methylation data. Our findings highlight the significance of epigenomic data, and they indicate integrating DNA methylation data with gene coexpression networks can have a synergistic effect.
| S-EPMC8294109 | biostudies-literature
Project description:We report herein that Sprouty-Related EVH1 Domain-Containing Protein1 (SPRED1) is downregulated and a prognostic biomarker in adult acute myeloid leukemia (AML). We determined mRNA levels of SPRED1 in the bone marrow mononuclear cells from adult patients, including 113 AMLs and 22 acute lymphoblastic leukemias (ALLs), as well as in 37 healthy control subjects. Significantly decreased SPRED1 mRNA expression was found in AML patients comparing to those in ALL patients and healthy controls, which was confirmed by immunocytochemistry analysis of SPRED1 protein and ELISA measurement of serum SPRED1 level. Further analysis demonstrated that SPRED1 expression was significantly higher for most patients at complete remission after induction treatment than at diagnosis. Moreover, SPRED1 expression was significantly downregulated in M2 and M3 types. Non-acute promyelocytic leukemia (non-APL) patients with decreased SPRED1 had significantly lower 2-year progression-free survival and event-free survival rates. In vitro, ectopic overexpression of SPRED1 leads to a decrease of extracellular signal-regulated kinase (ERK) phosphorylation, induction of apoptosis and reduction of proliferation of THP-1 cells. Our findings suggest SPRED1 is not only a predictor of treatment response, but also an independent prognostic factor for non-APL, and targeting Ras- Mitogen-activated protein kinase (MAPK) signaling may be a promising strategy for the treatment of AML with downregulation of SPRED1.
| S-EPMC7056905 | biostudies-literature
Project description:SIRT2 is a member of the NAD+ dependent deacetylases. In this study, the associations between SIRT2 expression and molecular and clinical characteristics of patients with acute myeloid leukemia (AML) were evaluated by data from The Cancer Genome Atlas. SIRT2 was overexpressed in the intermediate- and poor-risk groups of patients, compared to the favorable-risk group of patients (P = 0.002 and 0.004, respectively). High SIRT2 expression was associated with significantly shorter overall survival (OS; P = 0.0005) and event-free survival (EFS; P = 0.0002) than low SIRT2 expressio in a cohort of 167 patients with AML. Multivariate analyses revealed that high SIRT2 expression was associated with shorter OS (P = 0.031) and EFS (P = 0.020). Gene-expression profiling showed 259 differential expressed genes including CD4, CD14 and IL10. Gene sets like MAPK signaling pathway, VEGF signaling pathway and acute myeloid leukemia were upregulated in SIRT2(high) patients. We also found different methylation patterns in these two groups. OS and EFS of SIRT2(high) patients who did not undergo transplantation were significantly shorter than those of SIRT2(low) patients (P = 0.0120 and P = 0.0107, respectively). Taken together, these findings suggest that high SIRT2 expression is a novel and unfavorable prognostic biomarker for AML risk-stratification.
| S-EPMC4904374 | biostudies-literature
Project description:BACKGROUND:The aim of this study is to find the potential survival related DNA methylation signature capable of predicting survival time for acute myelocytic leukemia (AML) patients. METHODS:DNA methylation data were downloaded. DNA methylation signature was identified in the training group, and subsequently validated in an independent validation group. The overall survival of DNA methylation signature was performed. Functional analysis was used to explore the function of corresponding genes of DNA methylation signature. Differentially methylated sites and CpG islands were also identified in poor-risk group. RESULTS:A DNA methylation signature involving 8 DNA methylation sites and 6 genes were identified. Functional analysis showed that protein binding and cytoplasm were the only two enriched Gene Ontology terms. A total of 70 differentially methylated sites and 6 differentially methylated CpG islands were identified in poor-risk group. CONCLUSIONS:The identified survival related DNA methylation signature adds to the prognostic value of AML.
| S-EPMC6014658 | biostudies-literature
Project description:We hypothesized that DNA methylation distributes into specific patterns in cancer cells, which reflect critical biological differences. We therefore examined the methylation profiles of 344 patients with acute myeloid leukemia (AML). Clustering of these patients by methylation data segregated patients into 16 groups. Five of these groups defined new AML subtypes that shared no other known feature. In addition, DNA methylation profiles segregated patients with CEBPA aberrations from other subtypes of leukemia, defined four epigenetically distinct forms of AML with NPM1 mutations, and showed that established AML1-ETO, CBFb-MYH11, and PML-RARA leukemia entities are associated with specific methylation profiles. We report a 15 gene methylation classifier predictive of overall survival in an independent patient cohort (p < 0.001, adjusted for known covariates).
| S-EPMC3008568 | biostudies-literature