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  • DISEASE  (16)
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  • 1
    Keywords: CANCER ; EXPRESSION ; INHIBITOR ; proliferation ; CELL ; CELL-PROLIFERATION ; human ; QUANTIFICATION ; SYSTEM ; SYSTEMS ; TOOL ; DISEASE ; DISEASES ; GENE ; GENE-EXPRESSION ; SAMPLE ; SAMPLES ; TISSUE ; DNA ; MECHANISM ; TISSUES ; mechanisms ; BIOLOGY ; SEQUENCE ; SEQUENCES ; DISORDER ; SCHIZOPHRENIA ; NEOPLASIA ; PATTERNS ; gene expression ; DISRUPTION ; genetics ; REPRODUCIBILITY ; EFFICACY ; DNA methylation ; INSTABILITY ; UNITED-STATES ; ELECTROPHORESIS ; sensitivity ; METHYLATION ; GENOMIC INSTABILITY ; HYPERMETHYLATION ; INHIBITORS ; molecular biology ; HUMAN CANCER ; 5-methylcytosine ; cell proliferation ; CPG ISLANDS ; TECHNOLOGY ; microfluidics ; USA ; ACCURATE ; CANCER GENETICS ; epigenetic ; STATE ; Genetic ; ISLANDS ; RESTRICTION ; DNA/analysis/chemistry/genetics *DNA Methylation DNA Restriction Enzymes Electrophoresis,Polyacrylam ; METHYLATION INHIBITOR
    Abstract: DNA methylation is the best-studied epigenetic modification, and in mammals it describes the conversion of cytosine to 5-methylcytosine in the context of CpG dinucleotides. In recent years, it has become evident that epigenetic mechanisms are severely disrupted in human neoplasia, and evidence suggests that alterations of DNA methylation patterns may be an integral mechanism in the etiology of other diseases such as bipolar disorder and schizophrenia. The main effect of altered DNA methylation is the disruption of normal patterns of gene expression through genomic instability and hypermethylation of CpG islands, which together could lead to uncontrolled cell proliferation. DNA methylation can be reversed through pharmacological intervention via the systemic administration of DNA methylation inhibitors. Thus, the ability to accurately quantify DNA methylation levels in genomic sequences is a prerequisite to assess not only treatment efficacy, but also the effect of the DNA methylation inhibitors on bystander tissues. Several methods are currently available for the analysis of DNA methylation. Nonetheless, accurate and reproducible quantification of DNA methylation remains challenging. Here, we describe Bio-COBRA, a modified protocol for combined bisulfite restriction analysis (COBRA) that incorporates an electrophoresis step in microfluidics chips. Microfluidics technology involves the handling of small amounts of liquid in miniaturized systems. Bio-COBRA provides a platform for the rapid and quantitative assessment of DNA methylation patterns in large sample sets. Its sensitivity and reproducibility also make it an excellent tool for the analysis of DNA methylation in clinical samples
    Type of Publication: Journal article published
    PubMed ID: 18987820
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  • 2
    Keywords: APOPTOSIS ; CANCER ; CELLS ; EXPRESSION ; tumor ; CELL ; human ; MODEL ; DISEASE ; SITES ; GENE ; GENES ; transcription ; MICE ; NF-KAPPA-B ; COMPLEX ; COMPLEXES ; DNA ; MECHANISM ; murine ; TRANSCRIPTION FACTOR ; IMPACT ; animals ; mechanisms ; BINDING ; SEQUENCE ; SEQUENCES ; TARGET ; MOUSE ; STAGE ; TRANSCRIPTION FACTORS ; PROGRESSION ; MALIGNANCIES ; PATTERNS ; PROMOTER ; AGE ; transgenic ; leukemia ; DNA methylation ; TUMOR-SUPPRESSOR GENE ; REGION ; B-CELLS ; RECRUITMENT ; STRATEGIES ; MOUSE MODEL ; TARGETS ; REPRESSION ; METHYLATION ; TRANSCRIPTIONAL REPRESSION ; REGULATOR ; MALIGNANCY ; PROGRAM ; TUMOR-SUPPRESSOR ; CLL ; MURINE MODEL ; development ; BINDING-SITE ; USA ; EPIGENETICS ; ONSET ; CPG-ISLAND METHYLATION ; BINDING-SITES ; OCCURS ; tumor suppressor ; epigenetic ; STATE ; BINDING SITE ; histone modifications ; ABERRANT METHYLATION ; 3 ; therapeutic ; THERAPEUTIC TARGET ; WELL ; STRATEGY ; INVESTIGATE ; RATIONALE ; TRANSCRIPTION-FACTOR ; FOXD3
    Abstract: Epigenetic alterations, including gain or loss of DNA methylation, are a hallmark of nearly every malignancy. Changes in DNA methylation can impact expression of cancer-related genes including apoptosis regulators and tumor suppressors. Because such epigenetic changes are reversible, they are being aggressively investigated as potential therapeutic targets. Here we use the E mu-TCL1 transgenic mouse model of chronic lymphocytic leukemia (CLL) to determine the timing and patterns of aberrant DNA methylation, and to investigate the mechanisms that lead to aberrant DNA methylation. We show that CLL cells from E mu-TCL1 mice at various stages recapitulate epigenetic alterations seen in human CLL. Aberrant methylation of promoter sequences is observed as early as 3 months of age in these animals, well before disease onset. Abnormally methylated promoter regions include binding sites for the transcription factor FOXD3. We show that loss of Foxd3 expression due to an NF-kappa B p50/p50:HDAC1 repressor complex occurs in TCL1-positive B cells before methylation. Therefore, specific transcriptional repression is an early event leading to epigenetic silencing of target genes in murine and human CLL. These results provide strong rationale for the development of strategies to target NF-kappa B components in CLL and potentially other B-cell malignancies
    Type of Publication: Journal article published
    PubMed ID: 19666576
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  • 3
    Keywords: EXPRESSION ; TOXICITY ; VITRO ; DISEASE ; GENE ; GENES ; PATIENT ; DNA ; CYCLE ; TARGET ; TRIAL ; LYMPHOMA ; MALIGNANCIES ; DNA methylation ; ESCALATION ; METHYLATION ; HYPERMETHYLATION ; ACUTE MYELOID-LEUKEMIA ; non-Hodgkin lymphoma ; PHASE ; DECITABINE ; B-CELL ; chronic lymphocytic leukaemia ; hematopoietic malignancies ; 5-AZA-2'-DEOXYCYTIDINE ; non-Hodgkin ; epigenetic silencing ; HENT1 ; KINASE CPG ISLAND
    Abstract: P〉Targeting aberrant DNA hypermethylation in chronic lymphocytic leukaemia (CLL) and non-Hodgkin lymphoma (NHL) with decitabine may reverse epigenetic silencing in B-cell malignancies. Twenty patients were enrolled in two phase I trials to determine the minimum effective pharmacological dose of decitabine in patients with relapsed/refractory CLL (n = 16) and NHL (n = 4). Patients received 1-3 cycles of decitabine. Dose-limiting toxicity (DLT) was observed in 2 of 4 CLL and 2 of 2 NHL patients receiving decitabine at 15 mg/m2 per d days 1-10, consisting of grade 3-4 thrombocytopenia and hyperbilirubinaemia. Six patients with CLL received decitabine at 10 mg/m2 per d days 1-10 without DLT; however, re-expression of methylated genes or changes in global DNA methylation were not observed. Therefore, a 5-day decitabine schedule was examined. With 15 mg/m2 per d decitabine days 1-5, DLT occurred in 2 of 6 CLL and 2 of 2 NHL patients, consisting of grade 3-4 neutropenia, thrombocytopenia, and febrile neutropenia. Eight patients had stable disease. In 17 patients, there were no significant changes in genome-wide methylation or in target gene re-expression. In conclusion, dose-limiting myelosuppression and infectious complications prevented dose escalation of decitabine to levels associated with changes in global methylation or gene re-expression in CLL and NHL
    Type of Publication: Journal article published
    PubMed ID: 20456354
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  • 4
    Keywords: APOPTOSIS ; CANCER ; EXPRESSION ; proliferation ; SURVIVAL ; DISEASE ; GENE ; DIFFERENTIATION ; PATHOGENESIS ; B-CELLS ; CHRONIC LYMPHOCYTIC-LEUKEMIA ; ANIMAL-MODELS ; TUMOR-SUPPRESSOR ; fludarabine ; MURINE MODEL ; B-CELL LYMPHOCYTOSIS ; LIPOPROTEIN-LIPASE
    Abstract: Inhibitor of DNA binding protein 4 (ID4) is a member of the dominant-negative basic helix-loop-helix transcription factor family that lacks DNA binding activity and has tumor suppressor function. ID4 promoter methylation has been reported in acute myeloid leukemia and chronic lymphocytic leukemia (CLL), although the expression, function, and clinical relevance of this gene have not been characterized in either disease. We demonstrate that the promoter of ID4 is consistently methylated to various degrees in CLL cells, and increased promoter methylation in a univariable analysis correlates with shortened patient survival. However, ID4 mRNA and protein expression is uniformly silenced in CLL cells irrespective of the degree of promoter methylation. The crossing of ID4(+/-) mice with E mu-TCL1 mice triggers a more aggressive murine CLL as measured by lymphocyte count and inferior survival. Hemizygous loss of ID4 in nontransformed TCL1-positive B cells enhances cell proliferation triggered by CpG oligonucleotides and decreases sensitivity to dexamethasone-mediated apoptosis. Collectively, this study confirms the importance of the silencing of ID4 in murine and human CLL pathogenesis.
    Type of Publication: Journal article published
    PubMed ID: 21098398
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  • 5
    Keywords: LUNG-CANCER ; DISEASE ; RISK ; GENES ; GENOME ; SEQUENCE ; MASS-SPECTROMETRY ; NICOTINIC ACETYLCHOLINE-RECEPTORS ; CANCER SUSCEPTIBILITY LOCUS ; 15Q25.1
    Abstract: Genome-wide association studies have highlighted three major lung cancer susceptibility regions at 15q25.1, 5p15.33 and 6p21.33. To gain insight into the possible mechanistic relevance of the genes in these regions, we investigated the regulation of candidate susceptibility gene expression by epigenetic alterations in healthy and lung tumor tissues. For genes up or downregulated in lung tumors, the influence of genetic variants on DNA methylation was investigated and in vitro studies were performed. We analyzed 394 CpG units within 19 CpG islands in the susceptibility regions in a screening set of 34 patients. Significant findings were validated in an independent patient set (n=50) with available DNA and RNA. The most consistent overall DNA methylation difference between tumor and adjacent normal tissue on 15q25 was tumor hypomethylation in the promoter region of CHRNB4 with a median difference of 8% (P〈0.001), which resulted in overexpression of the transcript in tumors (P〈0.001). Confirming previous studies, we also found hypermethylation in CHRNA3 and telomerase reverse transcriptase (TERT) with significant expression changes. Decitabine treatment of H1299 cells resulted in reduced methylation levels in gene promoters, elevated transcript levels of CHRNB4 and CHRNA3, and a slight downregulation of TERT demonstrating epigenetic regulation of lung cancer cells. Single-nucleotide polymorphisms rs421629 on 5p15.33 and rs1948, rs660652, rs8040868 and rs2036527 on 15q25.1, previously identified as lung cancer risk or nicotine-addiction modifiers, were associated with tumor DNA methylation levels in the promoters of TERT and CHRNB4 (P〈0.001), respectively, in two independent sample sets (n=82; n=150). In addition, CHRNB4 knockdown in two different cell lines (A549 and H1299) resulted in reduced proliferation (P(A549)〈0.05;P(H1299)〈0.001) and propensity to form colonies in H1299 cells. These results suggest epigenetic deregulation of nicotinic acetylcholine receptor subunit (nAChR) genes which in the case of CHRNB4 is strongly associated with genetic lung cancer susceptibility variants and a functional impact on tumorigenic potential.Oncogene advance online publication, 3 September 2012; doi:10.1038/onc.2012.344.
    Type of Publication: Journal article published
    PubMed ID: 22945651
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  • 6
    Keywords: SURVIVAL ; DISEASE ; ABERRATIONS ; DNA methylation ; EVOLUTION ; CD38 EXPRESSION ; MUTATION STATUS ; AGREEMENT ; IBRUTINIB
    Abstract: ZAP-70 methylation 223 nucleotides downstream of transcription start (CpG+223) predicts outcome in chronic lymphocytic leukemia (CLL), but its impact relative to CD38 and ZAP-70 expression or immunoglobulin heavy chain variable region (IGHV) status is uncertain. Additionally, standardizing ZAP-70 expression analysis has been unsuccessful. CpG+223 methylation was quantitatively determined in 295 untreated CLL cases using MassARRAY. Impact on clinical outcome vs CD38 and ZAP-70 expression and IGHV status was evaluated. Cases with low methylation (〈20%) had significantly shortened time to first treatment (TT) and overall survival (OS) (P 〈 .0001). For TT, low methylation defined a large subset of ZAP-70 protein-negative cases with significantly shortened TT (median, 8.0 vs 3.9 years for high vs low methylation; hazard ratio [HR] = 0.43; 95% confidence interval [CI], 0.25-0.74). Conversely, 16 ZAP-70 protein-positive cases with high methylation had poor outcome (median, 1.1 vs 2.3 years for high vs low methylation; HR = 1.62; 95% CI, 0.87-3.03). For OS, ZAP-70 methylation was the strongest risk factor; CD38 and ZAP-70 expression or IGHV status did not significantly improve OS prediction. A pyrosequencing assay was established that reproduced the MassARRAY data (kappa coefficient 〉 0.90). Thus, ZAP-70 CpG+223 methylation represents a superior biomarker for TT and OS that can be feasibly measured, supporting its use in risk-stratifying CLL.
    Type of Publication: Journal article published
    PubMed ID: 24868078
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  • 7
    Keywords: CANCER ; CELLS ; EXPRESSION ; BLOOD ; CELL ; human ; KINASE ; DISEASE ; PROTEIN ; FAMILY ; TRANSCRIPTION FACTOR ; BINDING ; BIOLOGY ; MEMBER ; MEMBERS ; MOLECULAR-BIOLOGY ; protein kinase ; PROTEIN-KINASE ; NO ; CELL-DEATH ; PROMOTER ; MUTATION ; leukemia ; Jun ; PHENOTYPE ; METHYLATION ; molecular biology ; molecular ; PROGRAM ; RE ; FAMILIES ; ALLELE ; chronic lymphocytic leukemia ; CLL ; heritability ; HAPLOTYPE ; EVENTS ; PREDISPOSITION ; USA ; LOSSES ; PROMOTER METHYLATION ; B-CELL ; KINASE-1 ; REDUCED EXPRESSION ; TUMOR-SUPPRESSOR GENES ; CpG island ; CHRONIC-LYMPHOCYTIC-LEUKEMIA ; OCCURS ; death associated protein kinase 1 ; APOPTOTIC CHECKPOINT ; DNA HYPERMETHYLATION ; P2X7 RECEPTOR GENE
    Abstract: The heritability of B cell chronic lymphocytic leukemia (CLL) is relatively high; however, no predisposing mutation has been convincingly identified. We show that loss or reduced expression of death-associated protein kinase 1 (DAPK1) underlies cases of heritable predisposition to CLL and the majority of sporadic CLL. Epigenetic silencing of DAPK1 by promoter methylation occurs in almost all sporadic CLL cases. Furthermore, we defined a disease haplotype, which segregates with the CLL phenotype in a large family. DAM expression of the CLL allele is downregulated by 75% in germline cells due to increased HOXB7 binding. In the blood cells from affected family members, promoter methylation results in additional loss of DAM expression. Thus, reduced expression of DAM can result from germline predisposition, as well as epigenetic or somatic events causing or contributing to the CILL phenotype
    Type of Publication: Journal article published
    PubMed ID: 17540169
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  • 8
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    HNO 56 (6), 594-602 
    Keywords: CANCER ; EXPRESSION ; SURVIVAL ; tumor ; carcinoma ; CELL ; Germany ; THERAPY ; DISEASE ; NEW-YORK ; SITES ; GENE ; GENES ; DNA ; BIOMARKERS ; SEQUENCE ; SEQUENCES ; ALPHA ; prevention ; PROGRESSION ; ASSAY ; DNA methylation ; inactivation ; TUMOR-SUPPRESSOR GENE ; REGION ; REGIONS ; PHENOTYPE ; SQUAMOUS-CELL CARCINOMA ; HEAD ; CARCINOMAS ; STRATEGIES ; squamous cell carcinoma ; OUTCOMES ; HYPERMETHYLATION ; C/EBP-ALPHA ; molecular ; CELL CARCINOMA ; TUMOR-SUPPRESSOR ; THERAPIES ; CANDIDATE GENES ; HNSCC ; CPG ISLANDS ; biomarker ; SUPPRESSOR ; PROMOTER HYPERMETHYLATION ; USA ; LOSSES ; EPIGENETICS ; CANDIDATE ; CANCERS ; REDUCED EXPRESSION ; DNA-METHYLATION ; modification ; tumor suppressor ; epigenetic ; DNA METHYLATION PATTERNS
    Abstract: For years, head and neck squamous cell carcinomas (HNSCC) have been among the leading cancers worldwide. Despite considerable efforts, the 5-year survival rate for HNSCC has not changed significantly. To improve this situation, it is necessary to understand the fundamental biological processes leading to the disease and its progression. In addition to known genetic changes in HNSCC, molecular cytogenetic investigations have identified chromosomal regions of gains and losses, but many of the responsible candidate genes have yet to be identified. Furthermore, recent results indicate the importance of epigenetic modifications in HNSCC, such as DNA methylation. Several genes, including the tumor suppressor CDKN2A and other candidates such as DAPK1, MGMT, TIMP3, TCF21, and C/EBP alpha, have been found to harbor hypermethylated regulatory sequences that lead to reduced expression or gene silencing. Hypermethylation in such genes could be used not only as biomarkers for the early detection of HNSCC but also to improve prevention strategies and therapy outcomes
    Type of Publication: Journal article published
    PubMed ID: 18483718
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  • 9
    Keywords: APOPTOSIS ; EXPRESSION ; SURVIVAL ; DISEASE ; GENES ; LYMPHOMA ; CANCER-CELLS ; GUIDELINES ; MICRORNA ; LC3
    Abstract: Toxicity and relapses from the immunochemotherapy used to treat chronic lymphocytic leukemia (CLL) prompt continued interest in gentle but effective targeted treatment options for the mainly elderly population suffering from this disease. Here, we report the definition of critical CLL cell survival pathways that can be targeted by ectopic reexpression of the miRNA genes miR-130a and miR-143 which are widely downregulated in CLL. Notably, miR-130a inhibited autophagy by reducing autophagosome formation, an effect mediated by downregulation of the genes ATG2B and DICER1, the latter of which is a major component of the miRNA silencing machinery. In support of the concept of a fundamental connection between miRNA disregulation and altered autophagic flux in this cancer, we showed that RNA interference-mediated knockdown of DICER1 expression was sufficient to reduce autophagy in primary or established cultures of CLL cells. Together, our findings show that miR-130a modulates cell survival programs by regulating autophagic flux, and they define roles for miR-130a and Dicer1 in a regulatory feedback loop that mediates CLL cell survival. Cancer Res; 72(7); 1763-72. (c)2012 AACR.
    Type of Publication: Journal article published
    PubMed ID: 22350415
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  • 10
    Keywords: CANCER ; EXPRESSION ; SURVIVAL ; tumor ; carcinoma ; CELL ; LUNG ; MODEL ; THERAPY ; CLASSIFICATION ; lung cancer ; LUNG-CANCER ; DEATH ; DISEASE ; RISK ; PROTEIN ; SAMPLE ; SAMPLES ; transcription ; TUMORS ; PATIENT ; DNA ; TRANSCRIPTION FACTOR ; BREAST-CANCER ; TARGET ; STAGE ; IDENTIFICATION ; PATTERNS ; METASTASIS ; chemotherapy ; DNA methylation ; HETEROZYGOSITY ; PROGNOSTIC-FACTORS ; MULTIVARIATE ; CARCINOMAS ; PROGNOSTIC FACTORS ; adenocarcinoma ; ADENOCARCINOMAS ; squamous cell carcinoma ; TARGETS ; METHYLATION ; PROGNOSTIC FACTOR ; staging ; protein expression ; RELATIVE RISK ; CELL CARCINOMA ; SUBSET ; PATTERN ; THERAPIES ; overall survival ; LIBRARIES ; PROGNOSTIC-FACTOR ; CPG ISLANDS ; LEVEL ; INTERVAL ; methods ; EXPRESSION PROFILES ; ADJUVANT CHEMOTHERAPY ; USA ; NSCLC ; genomic ; SQUAMOUS-CELL ; PREDICT ; MEDICINE ; nonsmall cell lung cancer ; correlates ; DNA-METHYLATION ; scanning ; LONG ARM ; SQUAMOUS-CELL-CARCINOMAS
    Abstract: Background Lung cancer is the leading cause of cancer-related death worldwide. Currently, tumor, node, metastasis (TNM) staging provides the most accurate prognostic parameter for patients with non-small cell lung cancer (NSCLC). However, the overall survival of patients with resectable tumors varies significantly, indicating the need for additional prognostic factors to better predict the outcome of the disease, particularly within a given TNM subset. Methods and Findings In this study, we investigated whether adenocarcinomas and squamous cell carcinomas could be differentiated based on their global aberrant DNA methylation patterns. We performed restriction landmark genomic scanning on 40 patient samples and identified 47 DNA methylation targets that together could distinguish the two lung cancer subgroups. The protein expression of one of those targets, oligodendrocyte transcription factor 1 (OLIG1), significantly correlated with survival in NSCLC patients, as shown by univariate and multivariate analyses. Furthermore, the hazard ratio for patients negative for OLIG1 protein was significantly higher than the one for those patients expressing the protein, even at low levels. Conclusions Multivariate analyses of our data confirmed that OLIG1 protein expression significantly correlates with overall survival in NSCLC patients, with a relative risk of 0.84 (95% confidence interval 0.77-0.91, p 〈 0.001) along with T and N stages, as indicated by a Cox proportional hazard model. Taken together, our results suggests that OLIG1 protein expression could be utilized as a novel prognostic factor, which could aid in deciding which NSCLC patients might benefit from more aggressive therapy. This is potentially of great significance, as the addition of postoperative adjuvant chemotherapy in T2N0 NSCLC patients is still controversial
    Type of Publication: Journal article published
    PubMed ID: 17388669
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