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  • tumor  (19)
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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: 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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  • 5
    Keywords: CANCER ; EXPRESSION ; IN-VITRO ; tumor ; carcinoma ; CELL ; human ; IN-VIVO ; LUNG ; VITRO ; VIVO ; lung cancer ; LUNG-CANCER ; SITE ; GENE ; microarray ; PROTEIN ; SAMPLE ; SAMPLES ; transcription ; cell line ; DIFFERENTIATION ; LINES ; TIME ; DNA ; MECHANISM ; TRANSCRIPTION FACTOR ; MARKER ; prognosis ; mechanisms ; BINDING ; cell cycle ; CELL-CYCLE ; CELL-LINES ; CYCLE ; DOWN-REGULATION ; treatment ; ALPHA ; PROMOTER ; MUTATION ; CELL-LINE ; LINE ; DNA methylation ; HETEROZYGOSITY ; inactivation ; REGION ; US ; HEAD ; INVOLVEMENT ; NECK ; squamous cell carcinoma ; OVEREXPRESSION ; POOR-PROGNOSIS ; cell lines ; expression profiling ; METHYLATION ; CYCLE CONTROL ; C/EBP-ALPHA ; BINDING PROTEIN ; CELL CARCINOMA ; ONCOLOGY ; ENHANCER ; BINDING-PROTEIN ; RE ; TUMOR-SUPPRESSOR ; DEMETHYLATION ; HNSCC ; SUPPRESSOR ; USA ; LOSSES ; head and neck squamous cell carcinoma ; EPIGENETICS ; cancer research ; in vivo ; UPSTREAM REGULATORY REGION ; SQUAMOUS-CELL ; 5-AZA-2'-DEOXYCYTIDINE ; UPSTREAM ; DNA-METHYLATION ; cell cycle control ; INVOLUCRIN PROMOTER ACTIVITY
    Abstract: Tumor suppressor CCAAT enhancer binding protein a (C/EBP alpha) is a transcription factor involved in cell cycle control and cellular differentiation. In a recent study, microarray expression profiling on head and neck squamous cell carcinoma (HNSCC) samples identified significant C/EBP alpha down-regulation, correlating with poor prognosis. However, the mechanisms of C/EBP alpha down-regulation remained elusive. C/EBP alpha has been previously found to provide an antiproliferative role in lung cancer, and our laboratory showed that its down-regulation involves epigenetic mechanisms. This prompted us to investigate the involvement of epigenetics in down-regulating C/EBP alpha in HNSCC. Here, we show that C/EBP alpha is down-regulated in HNSCC by loss of heterozygosity and DNA methylation, but not by gene mutation. We found a consistently methylated upstream regulatory region (-1,399 bp to -1,253 bp in relation to the transcription start site) in 68% of the HNSCC tumor samples, and DNA demethylation using 5-aza-2'-deoxycytidine treatment was able to significantly restore C/EBP alpha mRNA expression in the HNSCC cell lines we tested. In addition, C/EBP alpha overexpression in a HNSCC cell line (SCC22B) revealed its ability to provide tumor suppressor activity in HNSCC in vitro and in vivo. In conclusion, we showed for the first time not only that C/EBP alpha has tumor suppressor activity in HNSCC, but also that it is down-regulated by DNA promoter methylation
    Type of Publication: Journal article published
    PubMed ID: 17510391
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  • 6
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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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  • 7
    Keywords: RECEPTOR ; CANCER ; EXPRESSION ; GROWTH ; GROWTH-FACTOR ; INHIBITOR ; tumor ; CELL ; FACTOR RECEPTOR ; INHIBITION ; KINASE ; COMMON ; GENE ; GENE-EXPRESSION ; GENES ; PROTEIN ; meningioma ; TUMORS ; DNA ; MECHANISM ; mechanisms ; PROTEIN-KINASE ; IDENTIFICATION ; PROGRESSION ; COPY NUMBER ; gene expression ; MUTATION ; CELL-LINE ; DNA methylation ; inactivation ; MUTATIONS ; METHYLATION ; EPIDERMAL-GROWTH-FACTOR ; signaling ; SAN-FRANCISCO ; TUMOR-SUPPRESSOR ; development ; LOCUS ; MENINGIOMAS ; USA ; epidermal growth factor receptor ; GROWTH-FACTOR-RECEPTOR ; LOCI ; ANAPLASTIC MENINGIOMAS ; tumor suppressor ; epigenetic ; ABERRANT METHYLATION ; Genetic ; METHYLATION INHIBITOR ; tumor grade ; EPIDERMAL-GROWTH ; CODING SEQUENCES ; COLONIES ; MENINGIOMA CELL-LINE ; METHYLATION STATUS ; restriction landmark genome scanning ; WNK2
    Abstract: Both genetic and epigenetic mechanisms contribute to meningioma development by altering gene expression and protein function. To determine the relative contribution of each mechanism to meningioma development, we used an integrative approach measuring copy number and DNA methylation changes genomewide. We found that genetic alterations affected 1.9%, 7.4%, and 13.3% of the 691 loci studied, whereas epigenetic mechanisms affected 5.4%, 9.9%, and 10.3% of these loci in grade I, II, and III meningiomas, respectively. Genetic and epigenetic mechanisms rarely involved the same locus in any given tumor. The predilection for epigenetic rather than genetic silencing was exemplified at the 5' CpG island of WNK2, a serine-threonine kinase gene on chromosome 9q22.31. WNK2 is known to negatively regulate epidermal growth factor receptor signaling via inhibition of MEK1 (mitogen-activated protein kinase kinase 1), and point mutations have been reported in WNK1, WNK2, WNK3, and WNK4. In meningiomas, WNK2 was aberrantly methylated in 83% and 71% of grade II and III meningiomas, respectively, but rarely in a total of 209 tumors from 13 other tumor types. Aberrant methylation of the CpG island was associated with decreased expression in primary tumors. WNK2 could be reactivated with a methylation inhibitor in IOMM-Lee, a meningioma cell line with a densely methylated WNK2 CpG island and lack of WNK2 expression. Expression of exogenous WNK2 inhibited colony formation, implicating it as a potential cell growth suppressor. These findings indicate that epigenetic mechanisms are common across meningiomas of all grades and that for specific genes such as WNK2, epigenetic alteration may be the dominant, grade-specific mechanism of gene inactivation. Neuro-Oncology 11, 414-422, 2009 (Posted to Neuro-Oncology [serial online], Doc. D08-00170, November 11, 2008. URL http://neuro-oncology.dukejournals.org; DOI: 10.1215/15228517-2008-096)
    Type of Publication: Journal article published
    PubMed ID: 19001526
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  • 8
    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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  • 9
    Keywords: CANCER ; CELLS ; EXPRESSION ; tumor ; TUMOR-CELLS ; CELL ; human ; IN-VIVO ; MODEL ; MODELS ; VIVO ; CLASSIFICATION ; COMMON ; DISEASE ; DISTINCT ; GENE ; SAMPLE ; SAMPLES ; transcription ; TISSUE ; TUMORS ; DNA ; MECHANISM ; mechanisms ; T cell ; T-CELL ; BIOLOGY ; SEQUENCE ; SEQUENCES ; SUSCEPTIBILITY ; BREAST-CANCER ; culture ; MOUSE ; STAGE ; PROGRESSION ; LYMPHOMA ; PATTERNS ; PROMOTER ; TUMOR PROGRESSION ; genetics ; COLORECTAL-CANCER ; DNA methylation ; inactivation ; p53 ; EVOLUTION ; PHENOTYPE ; MOUSE MODEL ; SELECTION ; specificity ; OVEREXPRESSION ; METHYLATION ; TUMOR CELLS ; heredity ; CHRONIC LYMPHOCYTIC-LEUKEMIA ; HYPERMETHYLATION ; HETEROGENEITY ; EPIGENETIC INACTIVATION ; targeting ; PROGRAM ; PATTERN ; TUMOR-SUPPRESSOR ; HUMAN CANCER ; ACUTE MYELOID-LEUKEMIA ; LIBRARIES ; CELL LYMPHOMA ; CPG ISLANDS ; GENE-TRANSCRIPTION ; development ; TUMOR-CELL ; SUPPRESSOR ; PROFILES ; EVENTS ; SIGNATURE ; DISEASE PROGRESSION ; USA ; CPG ISLAND HYPERMETHYLATION ; HUMAN CANCERS ; PROMOTER METHYLATION ; CANCERS ; in vivo ; genomic ; GENETIC ALTERATION ; RARE ; PREDICT ; CpG island ; MYC ; TUMOR-DEVELOPMENT ; DNA-METHYLATION ; scanning ; CELL LYMPHOMAS ; evidence ; TUMOR SUPPRESSORS ; CAUSAL ROLE ; DNA HYPOMETHYLATION
    Abstract: Hypermethylation of CpG islands is a common epigenetic alteration associated with cancer. Global patterns of hypermethylation are tumor-type specific and nonrandom. The biological significance and the underlying mechanisms of tumor-specific aberrant promoter methylation remain unclear, but some evidence suggests that this specificity involves differential sequence susceptibilities, the targeting of DNA methylation activity to specific promoter sequences, or the selection of rare DNA methylation events during disease progression. Using restriction landmark genomic scanning on samples derived from tissue culture and in vivo models of T cell lymphomas, we found that MYC overexpression gave rise to a specific signature of CpG island hypermethylation. This signature reflected gene transcription profiles and was detected only in advanced stages of disease. The further inactivation of the Pten, p53, and E2f2 tumor suppressors in MYC-induced lymphomas resulted in distinct and diagnostic CpG island methylation signatures. Our data suggest that tumor-specific DNA methylation in lymphomas arises as a result of the selection of rare DNA methylation events during the course of tumor development. This selection appears to be driven by the genetic configuration of tumor cells, providing experimental evidence for a causal role of DNA hypermethylation in tumor progression and an explanation for the tremendous epigenetic heterogeneity observed in the evolution of human cancers. The ability to predict genome-wide epigenetic silencing based on relatively few genetic alterations will allow for a more complete classification of tumors and understanding of tumor cell biology
    Type of Publication: Journal article published
    PubMed ID: 17907813
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  • 10
    Keywords: CANCER ; SURVIVAL ; tumor ; Germany ; LUNG ; CT ; DIAGNOSIS ; INFORMATION ; lung cancer ; LUNG-CANCER ; TOOL ; DEATH ; EPIDEMIOLOGY ; RISK ; GENE ; GENES ; GENOME ; EFFICIENCY ; TIME ; DNA ; MARKER ; RISK-FACTORS ; GENETIC POLYMORPHISMS ; BIOMARKERS ; BIOLOGY ; polymorphism ; POLYMORPHISMS ; FIELD ; BREAST-CANCER ; TARGET ; IDENTIFICATION ; LESIONS ; HEALTH ; ASSAY ; genetics ; CIGARETTE-SMOKING ; risk factors ; smoking ; PROSTATE-CANCER ; DNA methylation ; EFFICIENT ; MARKERS ; TUMOR-SUPPRESSOR GENE ; cancer risk ; HIGH-RISK ; genetic polymorphism ; TARGETS ; HISTONE DEACETYLASE ; non-small cell lung cancer ; BETA-CAROTENE ; ONCOLOGY ; RE ; genomics ; biomarker ; CANCER DEVELOPMENT ; methods ; ASSAYS ; HIGH-THROUGHPUT ; USA ; EPIGENETICS ; cancer research ; RISK-FACTOR ; CANCERS ; CANCER-RISK ; TOOLS ; FHIT GENE ; quantitative ; GENOME-WIDE ASSOCIATION ; modification ; POOLED-ANALYSIS ; MODIFIERS ; epigenetic ; ABERRANT PROMOTER METHYLATION
    Abstract: Lung cancer is the leading cause of cancer-related death and thus a major health problem. The efficiency of current treatment modalities for lung cancer depends strongly on the time of diagnosis, with better chances of survival if a tumor has been detected at an early stage. Thus, there is an urgent need for rapid and efficient early detection methods. Biomarkers represent a possible alternative to current, rather expensive, screening tools such as spiral computer tomography (CT), or may allow the identification of high risk groups for whom screening would be cost efficient. Although most lung cancers are the consequence of smoking, a substantial fraction of molecular-epidemiological studies point to high-prevalence, low-penctrance genetic polymorphisms as modifiers of environmental lung cancer risk. In the past the genomics field has also made significant advances in identifying genetic lesions that can now be harvested with the goal of identifying novel biomarkers for lung cancer. Furthermore, the importance of epigenetic changes that occur during lung cancer development has been reported, but has been underestimated in the past. Novel high-throughput, quantitative assays for the detection of DNA methylation or histone tail modifications are now applied, to search for alterations in the lung cancer genome and will identify novel cancer-related genes that may become attractive targets for treatment, provide new insight into the biology of lung cancers, and could also become useful biomarkers for the early detection of lung cancer in sputum, or may be used as prognostic markers. Thus, an integrative approach in lung cancer research combining epidemiological, genetic and epigenetic information becomes an important concept for the future. (C) 2008 Wiley-Liss, Inc
    Type of Publication: Journal article published
    PubMed ID: 18425819
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