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  • GENES  (26)
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  • 1
    Keywords: APOPTOSIS ; CANCER ; EXPRESSION ; GROWTH ; GROWTH-FACTOR ; SURVIVAL ; tumor ; carcinoma ; CELL ; Germany ; PATHWAY ; DIAGNOSIS ; RISK ; GENE ; GENES ; SAMPLE ; SAMPLES ; PATIENT ; DNA ; MARKER ; RISK-FACTORS ; CELL-LINES ; DOWN-REGULATION ; EXPRESSION ANALYSIS ; ASSAY ; risk factors ; RATES ; CELL-LINE ; DNA methylation ; MARKERS ; SIGNALING PATHWAY ; HOMOLOG ; BETA ; HEAD ; squamous cell carcinoma ; GROWTH-FACTOR-BETA ; OVEREXPRESSION ; HYPOXIA ; NECK-CANCER ; signaling ; CELL CARCINOMA ; ONCOLOGY ; RE ; TUMOR-SUPPRESSOR ; TUMORIGENESIS ; CANDIDATE GENES ; TRANSPORTER ; analysis ; SUPPRESSOR ; USA ; CANDIDATE ; cancer research ; RISK-FACTOR ; CANCERS ; B-CELL ; DNA-METHYLATION ; modification ; tumor suppressor ; epigenetic
    Abstract: Head and neck squamous cell carcinoma (HNSCC) is a very aggressive cancer. In advanced stages, the patient has poor chances of receiving effective treatment, and survival rates are low. To facilitate timely diagnosis and improve treatment, elucidation of early detection markers is crucial. DNA methylation markers are particularly advantageous because DNA methylation is an early event in tumorigenesis, and the epigenetic modification, 5-methylcytosine, is a stable mark. A genome-wide screen using Restriction Landmark Genomic Scanning found a set of genes that are most commonly methylated in head and neck cancers. Five candidate genes: septin 9 (SEPT9), sodium-coupled monocarboxylate transporter 1 (SLM8), functional smad-suppressing element on chromosome 18 (FUSSEL18), early B-cell factor 3 (EBF3), and iroquois homeobox 1 (IRX1) were methylated in 27% to 67% of the HNSCC patient samples tested. Furthermore, similar to 50% of the methylated tumor samples shared methylation between two of the five genes (most commonly between EBF3 and IRX-1), and 15% shared methylation between three of the five genes. Expression analysis revealed candidate gene down-regulation in 25% to 93% of the HNSCC samples, and 5-aza-2'-deoxycytidine treatment was able to restore expression in at least 2 of 5 HNSCC cell lines for all of the genes tested. Overexpression of the three most frequently down-regulated candidates, SLC5A8, IRX1, and EBF3, validated their tumor suppressor potential by growth curve analysis and colony formation assay. Interestingly, all of the candidates identified may be involved in the transforming growth factor beta signaling pathway, which is often disrupted in HNSCC
    Type of Publication: Journal article published
    PubMed ID: 18559491
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  • 2
    Keywords: CANCER ; CELLS ; EXPRESSION ; INHIBITOR ; tumor ; BLOOD ; CELL ; DEATH ; GENE ; GENE-EXPRESSION ; GENES ; LINES ; DNA ; MECHANISM ; CELL-LINES ; ACID ; TRANSPORT ; CHROMATIN ; chromatin remodeling ; gene expression ; CELL-DEATH ; PROMOTER ; CELL-LINE ; leukemia ; LINE ; DNA methylation ; acetylation ; HISTONE DEACETYLASE ; histone deacetylase inhibitor ; METHYLATION ; HYPERMETHYLATION ; NORMAL CYTOGENETICS ; TUMOR-SUPPRESSOR ; METHYLTRANSFERASE ; REARRANGEMENT ; TRANSPORTER ; ADULT PATIENTS ; cell death ; SUPPRESSOR ; PROMOTER HYPERMETHYLATION ; USA ; DECITABINE ; H4 ; GROUP-B ; DNA-METHYLATION ; response ; tumor suppressor ; epigenetic ; ABERRANT METHYLATION ; PARTIAL TANDEM DUPLICATION ; ALL-1
    Abstract: Posttranslationally modified histones and DNA hypermethylation frequently interplay to deregulate gene expression in cancer. We report that acute myeloid leukemia (AML) with an aberrant histone methyltransferase, the mixed lineage leukemia partial tandem duplication (MLL-PTD), exhibits increased global DNA methylation versus AML with MLL-wildtype (MLL-WT-, P =.02). Among the differentially methylated genes, the SLC5A8 tumor suppressor gene (TSG) was more frequently hypermethylated (P =.003). In MLL-PTD+ cell lines having SLC5A8 promoter hypermethylation, incubation with decitabine activated SLC5A8 expression. Ectopic SLC5A8 expression enhanced histones H3 and H4 acetylation in response to the histone deacetylase inhibitor, valproate, consistent with the encoded protein-SMCT1-short-chain fatty acid transport function. In addition, enhanced cell death was observed in SMCT1-expressing MLL-PTD+ AML cells treated with valproate. Within the majority of MLL-PTD AML is a mechanism in which DNA hypermethylation silences a TSG that, together with MLL-PTD, can contribute further to aberrant chromatin remodeling and altered gene expression
    Type of Publication: Journal article published
    PubMed ID: 18566324
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  • 3
    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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  • 4
    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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  • 5
    Keywords: CANCER ; CELLS ; EXPRESSION ; IN-VITRO ; INHIBITOR ; tumor ; TUMOR-CELLS ; carcinoma ; CELL ; COMBINATION ; MODEL ; VITRO ; SITE ; SITES ; GENE ; GENE-EXPRESSION ; GENES ; PROTEIN ; TISSUE ; LINES ; DNA ; CARCINOGENESIS ; BREAST ; breast cancer ; BREAST-CANCER ; PROGRESSION ; genetics ; DNA methylation ; inactivation ; PCR ; REGION ; TRANSFORMATION ; EPITHELIAL-CELLS ; CARCINOMAS ; NETHERLANDS ; histone deacetylase inhibitor ; METHYLATION ; HYPERMETHYLATION ; ESTRADIOL ; PATTERN ; SCIENCE ; CPG ISLANDS ; ESTROGEN ; 17-BETA-ESTRADIOL ; EPIGENETIC CHANGES ; MESENCHYMAL TRANSITION ; Genetic ; heregulin ; Cell transformation ; ERBB RECEPTOR FAMILY ; HISTONE-DEACETYLASE INHIBITORS ; Neuregulin
    Abstract: Epigenetic inactivation of genes by DNA hypermethylation plays an important role in carcinogenesis An in vitro model of human breast epithelial cell transformation was used to study epigenetic changes induced by estradiol during the neoplastic process Different stages of tumor initiation and progression are represented in this model being MCF-10F the normal stage; trMCF cells, the transformed stage, bsMCF cells, the invasive stage and, caMCF cells, the tumor stage Global methylation studies by restriction landmark genomic scanning (RLGS) showed an increased DNA methylation during the in the invasive and tumor stages Expression studies showed that NRG1 (neuregulin 1), CSS3 (chondroitin sulfate synthase 3) and SNIP (SNAP-25-interacting protein) were downregulated in the invasive and tumor cells. The transformed cells showed low expression of STXBP6(amysin)compared to the parental cells MCF-10F The treatment of these cells with the demethylating agent 5-aza-dC alone or in combination with the histone deacetylase inhibitor trichostatin increased the expression of NRG1, STXBP6, CSS3 and SNIP confirming that DNA methylation plays an Important role in the regulation of the expression of these genes The NRG1 exon 1 has a region located between -136 and +79 (considering +1, the translational initiation site) rich in CpG sites that was analyzed by methylation specific PCR (MSP) NRG1 exon 1 showed progressive changes in the methylation pattern associated with the progression of the neoplastic process in this model; NRG1 exon 1 was unmethylated in MCF-10F and trMCF cells, becoming hypermethylated in the invasive (bsMCF) and tumor (caMCF) stages Studies of human breast tissue samples showed that NRG1 exon 1 was partially methylated in 14 out of 17 (82.4%) invasive carcinomas although it was unmethylated in normal tissues (8 out of 10 normal breast tissue samples) Furthermore, NRG1 exon 1 was partially methylated in 9 out of 14(64.3%) morphologically normal tissue samples adjacent to invasive carcinomas. (C) 2010 Elsevier B V. All rights reserved
    Type of Publication: Journal article published
    PubMed ID: 20193695
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  • 6
    Keywords: APOPTOSIS ; GENES ; GENOME ; DOWN-REGULATION ; LYMPHOMA ; TARGETS ; METHYLATION ; HUMAN CANCER-CELLS ; epigenetic regulation ; SIGNATURES
    Abstract: Dysregulated microRNA (miRNA) expression contributes to the pathogenesis of hematopoietic malignancies, including chronic lymphocytic leukemia (CLL). However, an understanding of the mechanisms that cause aberrant miRNA transcriptional control is lacking. In this study, we comprehensively investigated the role and extent of miRNA epigenetic regulation in CLL. Genome-wide profiling conducted on 24 CLL and 10 healthy B cell samples revealed global DNA methylation patterns upstream of miRNA sequences that distinguished malignant from healthy cells and identified putative miRNA promoters. Integration of DNA methylation and miRNA promoter data led to the identification of 128 recurrent miRNA targets for aberrant promoter DNA methylation. DNA hypomethylation accounted for more than 60% of all aberrant promoter-associated DNA methylation in CLL, and promoter DNA hypomethylation was restricted to well-defined regions. Individual hyper- and hypomethylated promoters allowed discrimination of CLL samples from healthy controls. Promoter DNA methylation patterns were confirmed in an independent patient cohort, with 11 miRNAs consistently showing an inverse correlation between DNA methylation status and expression level. Together, our findings characterize the role of epigenetic changes in the regulation of miRNA transcription and create a repository of disease-specific promoter regions that may provide additional insights into the pathogenesis of CLL. Cancer Res; 72(15); 3775-85. (c)2012 AACR.
    Type of Publication: Journal article published
    PubMed ID: 22710432
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  • 7
    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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  • 8
    Keywords: PATHWAY ; GENES ; MUTATIONS ; CHILDREN ; CHILDHOOD ; GTPASE-ACTIVATING PROTEINS ; PTPN11 ; GAP1 FAMILY ; JMML
    Abstract: Aberrant DNA methylation at specific genetic loci is a key molecular feature of juvenile myelomonocytic leukemia (JMML) with poor prognosis. Using quantitative high-resolution mass spectrometry, we identified RASA4 isoform 2, which maps to chromosome 7 and encodes a member of the GAP1 family of GTPase-activating proteins for small G proteins, as a recurrent target of isoform-specific DNA hypermethylation in JMML (51% of 125 patients analyzed). RASA4 isoform 2 promoter methylation correlated with clinical parameters predicting poor prognosis (older age, elevated fetal hemoglobin), with higher risk of relapse after hematopoietic stem cell transplantation, and with PTPN11 mutation. The level of isoform 2 methylation increased in relapsed cases after transplantation. Interestingly, most JMML cases with monosomy 7 exhibited hypermethylation on the remaining RASA4 allele. The results corroborate the significance of epigenetic modifications in the phenotype of aggressive JMML.
    Type of Publication: Journal article published
    PubMed ID: 25147919
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  • 9
    Keywords: RECEPTOR ; CANCER ; GENES ; ASSOCIATION ; PHENOTYPE ; HETEROGENEITY ; N-MYC ; SIGNATURES ; ALK ; DNA METHYLATION DATA
    Abstract: Neuroblastoma is a malignancy of the developing sympathetic nervous system that is often lethal when relapse occurs. We here used whole-exome sequencing, mRNA expression profiling, array CGH and DNA methylation analysis to characterize 16 paired samples at diagnosis and relapse from individuals with neuroblastoma. The mutational burden significantly increased in relapsing tumors, accompanied by altered mutational signatures and reduced subclonal heterogeneity. Global allele frequencies at relapse indicated clonal mutation selection during disease progression. Promoter methylation patterns were consistent over disease course and were patient specific. Recurrent alterations at relapse included mutations in the putative CHD5 neuroblastoma tumor suppressor, chromosome 9p losses, DOCK8 mutations, inactivating mutations in PTPN14 and a relapse-specific activity pattern for the PTPN14 target YAP. Recurrent new mutations in HRAS, KRAS and genes mediating cell-cell interaction in 13 of 16 relapse tumors indicate disturbances in signaling pathways mediating mesenchymal transition. Our data shed light on genetic alteration frequency, identity and evolution in neuroblastoma.
    Type of Publication: Journal article published
    PubMed ID: 26121086
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  • 10
    Keywords: CELLS ; EXPRESSION ; CELL ; human ; NETWORKS ; SITE ; SITES ; DISTINCT ; GENE ; GENE-EXPRESSION ; GENES ; GENOME ; microarray ; RNA ; transcription ; LINES ; MECHANISM ; mechanisms ; IDENTIFICATION ; PATTERNS ; gene expression ; microarrays ; PROMOTER ; PROMOTERS ; genetics ; HUMAN GENOME ; HUMAN GENES ; METHYLATION ; heredity ; PATTERN ; GENOME-WIDE ANALYSIS ; ARRAY ; genomics ; RESOURCE ; analysis ; CHIP ; USA ; microbiology ; ENGLAND ; biotechnology ; PLATFORM ; BREAST-CANCER CELLS ; synthesis ; STATE ; GENOME-WIDE ; ESTROGEN-RECEPTOR-ALPHA ; TRANSCRIPTION INITIATION
    Abstract: Background: Independent lines of evidence suggested that a large fraction of human genes possess multiple promoters driving gene expression from distinct transcription start sites. Understanding which promoter is employed in which cellular context is required to unravel gene regulatory networks within the cell. Results: We have developed a custom microarray platform that tiles roughly 35,000 alternative putative promoters from nearly 7,000 genes in the human genome. To demonstrate the utility of this array platform, we have analyzed the patterns of promoter usage in 17 beta-estradiol (E2)-treated and untreated MCF7 cells and show widespread usage of alternative promoters. Most intriguingly, we show that the downstream promoter in E2-sensitive multiple promoter genes tends to be very close to the 3'-terminus of the gene, suggesting exotic mechanisms of expression regulation in these genes. Conclusion: The usage of alternative promoters greatly multiplies the transcriptional complexity available within the human genome. The fact that many of these promoters are incapable of driving the synthesis of a meaningful protein-encoding transcript further complicates the story
    Type of Publication: Journal article published
    PubMed ID: 18655706
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