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[PMID]: 25298611
[Au] Autor:Ozdemir O; Sari ME; Sen E; Kurt A; Ileri AB; Atalay CR
[Ad] Address:Department of Obstetrics and Gynecology, Ankara Numune Training and Research Hospital, Ankara, Turkey....
[Ti] Title:Sclerosing stromal tumour of the ovary: A case report and the review of literature.
[So] Source:Niger Med J;55(5):432-7, 2014 Sep.
[Is] ISSN:0300-1652
[Cp] Country of publication:Nigeria
[La] Language:eng
[Ab] Abstract:Sclerosing stromal tumours are rare benign ovarian neoplasms of the sex cord stromal that occur predominantly in the second and third decades of life. To date, 208 cases have been recorded in the literature. Most patients have menstrual irregularities and pelvic pain. Infertility and virilisation have also been described. In this article, histopathological features and differential diagnosis of the benign sclerosing stromal tumour were described together with the literature data. It is imperative to consider the differential diagnosis of a sclerozing stromal tumour of the ovary in a young woman with an ovarian tumour. A combination of morphological, immunohistochemical, radiological and clinical findings is needed in differentiating the tumour from thecoma, fibroma/fibrosarcoma, lipoid tumours and Krukenberg tumour.
[Pt] Publication type:JOURNAL ARTICLE
[Em] Entry month:1410
[Cu] Class update date: 141011
[Lr] Last revision date:141011
[Da] Date of entry for processing:141009
[St] Status:PubMed-not-MEDLINE
[do] DOI:10.4103/0300-1652.140391

  2 / 1915172 MEDLINE  
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[PMID]: 25298718
[Au] Autor:Hariram; Mohammad S; Malkunje LR; Singh N; Das S; Mehta G
[Ad] Address:Department of Oral and Maxillofacial Surgery, King George's Medical University, Lucknow, Uttar Pradesh, India.
[Ti] Title:Ameloblastoma of the anterior mandible.
[So] Source:Natl J Maxillofac Surg;5(1):47-50, 2014 Jan.
[Is] ISSN:0975-5950
[Cp] Country of publication:India
[La] Language:eng
[Ab] Abstract:Ameloblastoma or adamantinoma is the rarest of the three forms of tumor of the odontogenic type. They are benign, locally aggressive neoplasms arising from ameloblasts, which typically occur at the angle of the mandible, and are often associated with an un-erupted tooth and must, therefore, be differentiated from a dentigerous cyst which will be centered on the crown. When in the maxilla (less common), they are located in the premolar region, and can extend up in the maxillary sinus. Ameloblastoma is reported to constitute about 1-3% of tumors and cysts of the jaws. The tumor is by far more common in the mandible than in the maxilla and shows predilection for various parts of the mandible in different racial groups. The relative frequency of the mandible to maxilla is reported as varying from 80-20% to 99-1%. Here, we are representing a case of ameloblastoma of anterior mandible which was considered as a rare site of occurrence.
[Pt] Publication type:JOURNAL ARTICLE
[Em] Entry month:1410
[Cu] Class update date: 141011
[Lr] Last revision date:141011
[Da] Date of entry for processing:141009
[St] Status:PubMed-not-MEDLINE
[do] DOI:10.4103/0975-5950.140173

  3 / 1915172 MEDLINE  
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[PMID]: 25298786
[Au] Autor:Zagaria A; Anelli L; Coccaro N; Tota G; Casieri P; Cellamare A; Minervini A; Minervini CF; Brunetti C; Cumbo C; Specchia G; Albano F
[Ad] Address:Department of Emergency and Organ Transplantation (D.E.T.O.), Hematology Section - University of Bari, P.zza G. Cesare, 11 70124 Bari, Italy....
[Ti] Title:5'RUNX1-3'USP42 chimeric gene in acute myeloid leukemia can occur through an insertion mechanism rather than translocation and may be mediated by genomic segmental duplications.
[So] Source:Mol Cytogenet;7(1):66, 2014.
[Is] ISSN:1755-8166
[Cp] Country of publication:England
[La] Language:eng
[Ab] Abstract:BACKGROUND: The runt-related transcription factor 1 (RUNX1) gene is a transcription factor that acts as a master regulator of hematopoiesis and represents one of the most frequent targets of chromosomal rearrangements in human leukemias. The t(7;21)(p22;q22) rearrangement generating a 5'RUNX1-3'USP42 fusion transcript has been reported in two cases of pediatric acute myeloid leukemia (AML) and further in eight adult cases of myeloid neoplasms. We describe the first case of adult AML with a 5'RUNX1-3'USP42 fusion gene generated by an insertion event instead of chromosomal translocation. METHODS: Conventional and molecular cytogenetic analyses allowed the precise characterization of the chromosomal rearrangement and breakpoints identification. Gene expression analysis was performed by quantitative real-time PCR experiments, whereas bioinformatic studies were carried out for revealing structural genomic characteristics of breakpoint regions. RESULTS: We identified an adult AML case bearing a ins(21;7)(q22;p15p22) generating a 5'RUNX1-3'USP42 fusion gene on der(21) chromosome and causing USP42 gene over-expression. Bioinformatic analysis of the genomic regions involved in ins(21;7)/t(7;21) showed the presence of interchromosomal segmental duplications (SDs) next to the USP42 and RUNX1 genes, that may underlie a non-allelic homologous recombination between chromosome 7 and 21 in AML. CONCLUSIONS: We report the first case of a 5'RUNX1-3'USP42 chimeric gene generated by a chromosomal cryptic insertion in an adult AML patient. Our data revealed that there may be a pivotal role for SDs in this very rare but recurrent chromosomal rearrangement.
[Pt] Publication type:JOURNAL ARTICLE
[Em] Entry month:1410
[Cu] Class update date: 141011
[Lr] Last revision date:141011
[Da] Date of entry for processing:141009
[St] Status:PubMed-not-MEDLINE
[do] DOI:10.1186/s13039-014-0066-7

  4 / 1915172 MEDLINE  
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[PMID]: 25291362
[Au] Autor:Demir H; Donner I; Kivipelto L; Kuismin O; Schalin-Jäntti C; De Menis E; Karhu A
[Ad] Address:Department of Medical Genetics, Genome-Scale Biology Research Program, Institute of Biomedicine, Biomedicum Helsinki, University of Helsinki, Helsinki, Finland....
[Ti] Title:Mutation Analysis of Inhibitory Guanine Nucleotide Binding Protein Alpha (GNAI) Loci in Young and Familial Pituitary Adenomas.
[So] Source:PLoS One;9(10):e109897, 2014.
[Is] ISSN:1932-6203
[Cp] Country of publication:United States
[La] Language:eng
[Ab] Abstract:Pituitary adenomas are neoplasms of the anterior pituitary lobe and account for 15-20% of all intracranial tumors. Although most pituitary tumors are benign they can cause severe symptoms related to tumor size as well as hypopituitarism and/or hypersecretion of one or more pituitary hormones. Most pituitary adenomas are sporadic, but it has been estimated that 5% of patients have a familial background. Germline mutations of the tumor suppressor gene aryl hydrocarbon receptor-interacting protein (AIP) predispose to hereditary pituitary neoplasia. Recently, it has been demonstrated that AIP mutations predispose to pituitary tumorigenesis through defective inhibitory GTP binding protein (Gαi) signaling. This finding prompted us to examine whether germline loss-of-function mutations in inhibitory guanine nucleotide (GTP) binding protein alpha (GNAI) loci are involved in genetic predisposition of pituitary tumors. To our knowledge, this is the first time GNAI genes are sequenced in order to examine the occurrence of inactivating germline mutations. Thus far, only somatic gain-of-function hot-spot mutations have been studied in these loci. Here, we have analyzed the coding regions of GNAI1, GNAI2, and GNAI3 in a set of young sporadic somatotropinoma patients (n = 32; mean age of diagnosis 32 years) and familial index cases (n = 14), thus in patients with a disease phenotype similar to that observed in AIP mutation carriers. In addition, expression of Gαi proteins was studied in human growth hormone (GH), prolactin (PRL), adrenocorticotropic hormone (ACTH)-secreting and non-functional pituitary tumors. No pathogenic germline mutations affecting the Gαi proteins were detected. The result suggests that loss-of-function mutations of GNAI loci are rare or nonexistent in familial pituitary adenomas.
[Pt] Publication type:JOURNAL ARTICLE
[Em] Entry month:1410
[Js] Journal subset:IM
[St] Status:In-Data-Review
[do] DOI:10.1371/journal.pone.0109897

  5 / 1915172 MEDLINE  
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[PMID]: 24971906
[Au] Autor:Peters DE; Hoover B; Cloud LG; Liu S; Molinolo AA; Leppla SH; Bugge TH
[Ad] Address:Proteases and Tissue Remodeling Section, Oral and Pharyngeal Cancer Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD, USA; Program of Pharmacology and Experimental Therapeutics, Tufts University School of Medicine, Boston, MA, USA....
[Ti] Title:Comparative toxicity and efficacy of engineered anthrax lethal toxin variants with broad anti-tumor activities.
[So] Source:Toxicol Appl Pharmacol;279(2):220-9, 2014 Sep 1.
[Is] ISSN:1096-0333
[Cp] Country of publication:United States
[La] Language:eng
[Ab] Abstract:We have previously designed and characterized versions of anthrax lethal toxin that are selectively cytotoxic in the tumor microenvironment and which display broad and potent anti-tumor activities in vivo. Here, we have performed the first direct comparison of the safety and efficacy of three engineered anthrax lethal toxin variants requiring activation by either matrix-metalloproteinases (MMPs), urokinase plasminogen activator (uPA) or co-localized MMP/uPA activities. C57BL/6J mice were challenged with six doses of engineered toxins via intraperitoneal (I.P.) or intravenous (I.V.) dose routes to determine the maximum tolerated dose for six administrations (MTD6) and dose-limiting toxicities. Efficacy was evaluated using the B16-BL6 syngraft model of melanoma; mice bearing established tumors were treated with six I.P. doses of toxin and tumor measurements and immunohistochemistry, paired with terminal blood work, were used to elaborate upon the anti-tumor mechanism and relative efficacy of each variant. We found that MMP-, uPA- and dual MMP/uPA-activated anthrax lethal toxins exhibited the same dose-limiting toxicity; dose-dependent GI toxicity. In terms of efficacy, all three toxins significantly reduced primary B16-BL6 tumor burden, ranging from 32% to 87% reduction, and they also delayed disease progression as evidenced by dose-dependent normalization of blood work values. While target organ toxicity and effective doses were similar amongst the variants, the dual MMP/uPA-activated anthrax lethal toxin exhibited the highest I.P. MTD6 and was 1.5-3-fold better tolerated than the single MMP- and uPA-activated toxins. Overall, we demonstrate that this dual MMP/uPA-activated anthrax lethal toxin can be administered safely and is highly effective in a preclinical model of melanoma. This modified bacterial cytotoxin is thus a promising candidate for further clinical development and evaluation for use in treating human cancers.
[Mh] MeSH terms primary: Antigens, Bacterial/pharmacology
Antineoplastic Agents/pharmacology
Bacterial Toxins/pharmacology
Melanoma, Experimental/drug therapy
Prodrugs/pharmacology
Protein Engineering
Skin Neoplasms/drug therapy
[Mh] MeSH terms secundary: Animals
Antigens, Bacterial/administration & dosage
Antigens, Bacterial/genetics
Antigens, Bacterial/metabolism
Antigens, Bacterial/toxicity
Antineoplastic Agents/administration & dosage
Antineoplastic Agents/metabolism
Antineoplastic Agents/toxicity
Bacterial Toxins/administration & dosage
Bacterial Toxins/genetics
Bacterial Toxins/metabolism
Bacterial Toxins/toxicity
Dose-Response Relationship, Drug
Female
Injections, Intraperitoneal
Injections, Intravenous
Matrix Metalloproteinases/metabolism
Maximum Tolerated Dose
Melanoma, Experimental/blood
Melanoma, Experimental/enzymology
Melanoma, Experimental/pathology
Mice
Mice, Inbred C57BL
Prodrugs/administration & dosage
Prodrugs/metabolism
Prodrugs/toxicity
Skin Neoplasms/blood
Skin Neoplasms/enzymology
Skin Neoplasms/pathology
Time Factors
Tumor Burden/drug effects
Tumor Markers, Biological/blood
Urokinase-Type Plasminogen Activator/metabolism
[Pt] Publication type:COMPARATIVE STUDY; JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., INTRAMURAL
[Nm] Name of substance:0 (Antigens, Bacterial); 0 (Antineoplastic Agents); 0 (Bacterial Toxins); 0 (Prodrugs); 0 (Tumor Markers, Biological); 0 (anthrax toxin); EC 3.4.21.73 (Urokinase-Type Plasminogen Activator); EC 3.4.24.- (Matrix Metalloproteinases)
[Em] Entry month:1410
[Js] Journal subset:IM
[Da] Date of entry for processing:140818
[St] Status:MEDLINE

  6 / 1915172 MEDLINE  
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[PMID]: 25128497
[Au] Autor:Huang CH; Lujambio A; Zuber J; Tschaharganeh DF; Doran MG; Evans MJ; Kitzing T; Zhu N; de Stanchina E; Sawyers CL; Armstrong SA; Lewis JS; Sherr CJ; Lowe SW
[Ad] Address:Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA; Cell and Developmental Biology Program, Weill Graduate School of Medical Sciences, Cornell University, New York, New York 10065, USA; Cold Spring Harbor Laboratory, Cold Spring Harbor, New York 11724, USA;...
[Ti] Title:CDK9-mediated transcription elongation is required for MYC addiction in hepatocellular carcinoma.
[So] Source:Genes Dev;28(16):1800-14, 2014 Aug 15.
[Is] ISSN:1549-5477
[Cp] Country of publication:United States
[La] Language:eng
[Ab] Abstract:One-year survival rates for newly diagnosed hepatocellular carcinoma (HCC) are <50%, and unresectable HCC carries a dismal prognosis owing to its aggressiveness and the undruggable nature of its main genetic drivers. By screening a custom library of shRNAs directed toward known drug targets in a genetically defined Myc-driven HCC model, we identified cyclin-dependent kinase 9 (Cdk9) as required for disease maintenance. Pharmacological or shRNA-mediated CDK9 inhibition led to robust anti-tumor effects that correlated with MYC expression levels and depended on the role that both CDK9 and MYC exert in transcription elongation. Our results establish CDK9 inhibition as a therapeutic strategy for MYC-overexpressing liver tumors and highlight the relevance of transcription elongation in the addiction of cancer cells to MYC.
[Mh] MeSH terms primary: Carcinoma, Hepatocellular/enzymology
Cyclin-Dependent Kinase 9/metabolism
Liver Neoplasms/enzymology
Proto-Oncogene Proteins c-myc/metabolism
Transcription Elongation, Genetic/physiology
[Mh] MeSH terms secundary: Animals
Carcinoma, Hepatocellular/genetics
Carcinoma, Hepatocellular/pathology
Cell Line, Tumor
Cell Proliferation
Female
Gene Expression
Gene Library
Hep G2 Cells
Humans
Liver Neoplasms/genetics
Liver Neoplasms/pathology
Mice
Positive Transcriptional Elongation Factor B/genetics
Positive Transcriptional Elongation Factor B/metabolism
Proto-Oncogene Proteins c-myc/genetics
RNA Interference
RNA, Small Interfering/metabolism
[Pt] Publication type:JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Name of substance:0 (Myc protein, mouse); 0 (Proto-Oncogene Proteins c-myc); 0 (RNA, Small Interfering); EC 2.7.11.- (Positive Transcriptional Elongation Factor B); EC 2.7.11.22 (Cyclin-Dependent Kinase 9)
[Em] Entry month:1410
[Cu] Class update date: 141011
[Lr] Last revision date:141011
[Js] Journal subset:IM
[Da] Date of entry for processing:140816
[St] Status:MEDLINE
[do] DOI:10.1101/gad.244368.114

  7 / 1915172 MEDLINE  
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[PMID]: 25106096
[Au] Autor:Zhang J; Wu LY; Zhang XS; Zhang S
[Ad] Address:National Center for Mathematics and Interdisciplinary Sciences, Academy of Mathematics and Systems Science, Chinese Academy of Sciences, Beijing 100190, China. zjh@amt.ac.cn.
[Ti] Title:Discovery of co-occurring driver pathways in cancer.
[So] Source:BMC Bioinformatics;15:271, 2014.
[Is] ISSN:1471-2105
[Cp] Country of publication:England
[La] Language:eng
[Ab] Abstract:BACKGROUND: It has been widely realized that pathways rather than individual genes govern the course of carcinogenesis. Therefore, discovering driver pathways is becoming an important step to understand the molecular mechanisms underlying cancer and design efficient treatments for cancer patients. Previous studies have focused mainly on observation of the alterations in cancer genomes at the individual gene or single pathway level. However, a great deal of evidence has indicated that multiple pathways often function cooperatively in carcinogenesis and other key biological processes. RESULTS: In this study, an exact mathematical programming method was proposed to de novo identify co-occurring mutated driver pathways (CoMDP) in carcinogenesis without any prior information beyond mutation profiles. Two possible properties of mutations that occurred in cooperative pathways were exploited to achieve this: (1) each individual pathway has high coverage and high exclusivity; and (2) the mutations between the pair of pathways showed statistically significant co-occurrence. The efficiency of CoMDP was validated first by testing on simulated data and comparing it with a previous method. Then CoMDP was applied to several real biological data including glioblastoma, lung adenocarcinoma, and ovarian carcinoma datasets. The discovered co-occurring driver pathways were here found to be involved in several key biological processes, such as cell survival and protein synthesis. Moreover, CoMDP was modified to (1) identify an extra pathway co-occurring with a known pathway and (2) detect multiple significant co-occurring driver pathways for carcinogenesis. CONCLUSIONS: The present method can be used to identify gene sets with more biological relevance than the ones currently used for the discovery of single driver pathways.
[Mh] MeSH terms primary: Carcinogenesis/genetics
Neoplasms/genetics
Neoplasms/pathology
Software
Systems Biology/methods
[Mh] MeSH terms secundary: Algorithms
Disease Progression
Humans
Mutation
Signal Transduction/genetics
[Pt] Publication type:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Em] Entry month:1410
[Js] Journal subset:IM
[Da] Date of entry for processing:140815
[St] Status:MEDLINE
[do] DOI:10.1186/1471-2105-15-271

  8 / 1915172 MEDLINE  
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[PMID]: 25069957
[Au] Autor:Wang T; Gu J; Li Y
[Ti] Title:Inferring the perturbed microRNA regulatory networks from gene expression data using a network propagation based method.
[So] Source:BMC Bioinformatics;15:255, 2014.
[Is] ISSN:1471-2105
[Cp] Country of publication:England
[La] Language:eng
[Ab] Abstract:BACKGROUND: MicroRNAs (miRNAs) are a class of endogenous small regulatory RNAs. Identifications of the dys-regulated or perturbed miRNAs and their key target genes are important for understanding the regulatory networks associated with the studied cellular processes. Several computational methods have been developed to infer the perturbed miRNA regulatory networks by integrating genome-wide gene expression data and sequence-based miRNA-target predictions. However, most of them only use the expression information of the miRNA direct targets, rarely considering the secondary effects of miRNA perturbation on the global gene regulatory networks. RESULTS: We proposed a network propagation based method to infer the perturbed miRNAs and their key target genes by integrating gene expressions and global gene regulatory network information. The method used random walk with restart in gene regulatory networks to model the network effects of the miRNA perturbation. Then, it evaluated the significance of the correlation between the network effects of the miRNA perturbation and the gene differential expression levels with a forward searching strategy. Results show that our method outperformed several compared methods in rediscovering the experimentally perturbed miRNAs in cancer cell lines. Then, we applied it on a gene expression dataset of colorectal cancer clinical patient samples and inferred the perturbed miRNA regulatory networks of colorectal cancer, including several known oncogenic or tumor-suppressive miRNAs, such as miR-17, miR-26 and miR-145. CONCLUSIONS: Our network propagation based method takes advantage of the network effect of the miRNA perturbation on its target genes. It is a useful approach to infer the perturbed miRNAs and their key target genes associated with the studied biological processes using gene expression data.
[Mh] MeSH terms primary: Gene Expression Profiling
Gene Regulatory Networks
MicroRNAs/genetics
Systems Biology/methods
[Mh] MeSH terms secundary: Carcinogenesis
Cell Line, Tumor
Colorectal Neoplasms/genetics
Colorectal Neoplasms/pathology
Gene Expression Regulation, Neoplastic
Humans
[Pt] Publication type:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Name of substance:0 (MicroRNAs)
[Em] Entry month:1410
[Js] Journal subset:IM
[Da] Date of entry for processing:140808
[St] Status:MEDLINE
[do] DOI:10.1186/1471-2105-15-255

  9 / 1915172 MEDLINE  
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[PMID]: 24739390
[Au] Autor:Nye MD; Almada LL; Fernandez-Barrena MG; Marks DL; Elsawa SF; Vrabel A; Tolosa EJ; Ellenrieder V; Fernandez-Zapico ME
[Ad] Address:From the Schulze Center for Novel Therapeutics, Division of Oncology Research, Mayo Clinic, Rochester, Minnesota 55905....
[Ti] Title:The transcription factor GLI1 interacts with SMAD proteins to modulate transforming growth factor ß-induced gene expression in a p300/CREB-binding protein-associated factor (PCAF)-dependent manner.
[So] Source:J Biol Chem;289(22):15495-506, 2014 May 30.
[Is] ISSN:1083-351X
[Cp] Country of publication:United States
[La] Language:eng
[Ab] Abstract:The biological role of the transcription factor GLI1 in the regulation of tumor growth is well established; however, the molecular events modulating this phenomenon remain elusive. Here, we demonstrate a novel mechanism underlying the role of GLI1 as an effector of TGFß signaling in the regulation of gene expression in cancer cells. TGFß stimulates GLI1 activity in cancer cells and requires its transcriptional activity to induce BCL2 expression. Analysis of the mechanism regulating this interplay identified a new transcriptional complex including GLI1 and the TGFß-regulated transcription factor, SMAD4. We demonstrate that SMAD4 physically interacts with GLI1 for concerted regulation of gene expression and cellular survival. Activation of the TGFß pathway induces GLI1-SMAD4 complex binding to the BCL2 promoter whereas disruption of the complex through SMAD4 RNAi depletion impairs GLI1-mediated transcription of BCL2 and cellular survival. Further characterization demonstrated that SMAD2 and the histone acetyltransferase, PCAF, participate in this regulatory mechanism. Both proteins bind to the BCL2 promoter and are required for TGFß- and GLI1-stimulated gene expression. Moreover, SMAD2/4 RNAi experiments showed that these factors are required for the recruitment of GLI1 to the BCL2 promoter. Finally, we determined whether this novel GLI1 transcriptional pathway could regulate other TGFß targets. We found that two additional TGFß-stimulated genes, INTERLEUKIN-7 and CYCLIN D1, are dependent upon the intact GLI1-SMAD-PCAF complex for transcriptional activation. Collectively, these results define a novel epigenetic mechanism that uses the transcription factor GLI1 and its associated complex as a central effector to regulate gene expression in cancer cells.
[Mh] MeSH terms primary: Carcinoma, Pancreatic Ductal/genetics
Pancreatic Neoplasms/genetics
Smad4 Protein/metabolism
Transcription Factors/metabolism
Transforming Growth Factor beta1/metabolism
p300-CBP Transcription Factors/metabolism
[Mh] MeSH terms secundary: Carcinoma, Pancreatic Ductal/metabolism
Cell Line, Tumor
Epigenesis, Genetic/physiology
Gene Expression Regulation, Neoplastic
Humans
Pancreatic Neoplasms/metabolism
Proto-Oncogene Proteins c-bcl-2/genetics
Signal Transduction/physiology
Smad2 Protein/genetics
Smad2 Protein/metabolism
Smad3 Protein/genetics
Smad3 Protein/metabolism
Smad4 Protein/genetics
Transcription Factors/genetics
Transforming Growth Factor beta1/genetics
[Pt] Publication type:JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Name of substance:0 (GLI1 protein, human); 0 (Proto-Oncogene Proteins c-bcl-2); 0 (SMAD2 protein, human); 0 (SMAD3 protein, human); 0 (SMAD4 protein, human); 0 (Smad2 Protein); 0 (Smad3 Protein); 0 (Smad4 Protein); 0 (Transcription Factors); 0 (Transforming Growth Factor beta1); EC 2.3.1.48 (p300-CBP Transcription Factors); EC 2.3.1.48 (p300-CBP-associated factor)
[Em] Entry month:1410
[Cu] Class update date: 141011
[Lr] Last revision date:141011
[Js] Journal subset:IM
[Da] Date of entry for processing:140729
[St] Status:MEDLINE
[do] DOI:10.1074/jbc.M113.545194

  10 / 1915172 MEDLINE  
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[PMID]: 24994026
[Au] Autor:Wahl S; Fenske N; Zeilinger S; Suhre K; Gieger C; Waldenberger M; Grallert H; Schmid M
[Ad] Address:Research Unit of Molecular Epidemiology, Helmholtz Zentrum München - German Research Center for Environmental Health, Ingolstädter Landstrasse 1, 85764 Neuherberg, Germany. simone.wahl@helmholtz-muenchen.de.
[Ti] Title:On the potential of models for location and scale for genome-wide DNA methylation data.
[So] Source:BMC Bioinformatics;15:232, 2014.
[Is] ISSN:1471-2105
[Cp] Country of publication:England
[La] Language:eng
[Ab] Abstract:BACKGROUND: With the help of epigenome-wide association studies (EWAS), increasing knowledge on the role of epigenetic mechanisms such as DNA methylation in disease processes is obtained. In addition, EWAS aid the understanding of behavioral and environmental effects on DNA methylation. In terms of statistical analysis, specific challenges arise from the characteristics of methylation data. First, methylation ß-values represent proportions with skewed and heteroscedastic distributions. Thus, traditional modeling strategies assuming a normally distributed response might not be appropriate. Second, recent evidence suggests that not only mean differences but also variability in site-specific DNA methylation associates with diseases, including cancer. The purpose of this study was to compare different modeling strategies for methylation data in terms of model performance and performance of downstream hypothesis tests. Specifically, we used the generalized additive models for location, scale and shape (GAMLSS) framework to compare beta regression with Gaussian regression on raw, binary logit and arcsine square root transformed methylation data, with and without modeling a covariate effect on the scale parameter. RESULTS: Using simulated and real data from a large population-based study and an independent sample of cancer patients and healthy controls, we show that beta regression does not outperform competing strategies in terms of model performance. In addition, Gaussian models for location and scale showed an improved performance as compared to models for location only. The best performance was observed for the Gaussian model on binary logit transformed ß-values, referred to as M-values. Our results further suggest that models for location and scale are specifically sensitive towards violations of the distribution assumption and towards outliers in the methylation data. Therefore, a resampling procedure is proposed as a mode of inference and shown to diminish type I error rate in practically relevant settings. We apply the proposed method in an EWAS of BMI and age and reveal strong associations of age with methylation variability that are validated in an independent sample. CONCLUSIONS: Models for location and scale are promising tools for EWAS that may help to understand the influence of environmental factors and disease-related phenotypes on methylation variability and its role during disease development.
[Mh] MeSH terms primary: DNA Methylation
Genomics/methods
Models, Statistical
[Mh] MeSH terms secundary: Case-Control Studies
CpG Islands/genetics
Epigenesis, Genetic
Humans
Neoplasms/genetics
Normal Distribution
[Pt] Publication type:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Em] Entry month:1410
[Js] Journal subset:IM
[Da] Date of entry for processing:140723
[St] Status:MEDLINE
[do] DOI:10.1186/1471-2105-15-232


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