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Search Results: 1 - 10 of 743 matches for " Reiner Siebert "
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Cancer initiation with epistatic interactions between driver and passenger mutations
Benedikt Bauer,Reiner Siebert,Arne Traulsen
Quantitative Biology , 2013, DOI: 10.1016/j.jtbi.2014.05.018
Abstract: We investigate the dynamics of cancer initiation in a mathematical model with one driver mutation and several passenger mutations. Our analysis is based on a multi type branching process: We model individual cells which can either divide or undergo apoptosis. In case of a cell division, the two daughter cells can mutate, which potentially confers a change in fitness to the cell. In contrast to previous models, the change in fitness induced by the driver mutation depends on the genetic context of the cell, in our case on the number of passenger mutations. The passenger mutations themselves have no or only a very small impact on the cell's fitness. While our model is not designed as a specific model for a particular cancer, the underlying idea is motivated by clinical and experimental observations in Burkitt Lymphoma. In this tumor, the hallmark mutation leads to deregulation of the MYC oncogene which increases the rate of apoptosis, but also the proliferation rate of cells. This increase in the rate of apoptosis hence needs to be overcome by mutations affecting apoptotic pathways, naturally leading to an epistatic fitness landscape. This model shows a very interesting dynamical behavior which is distinct from the dynamics of cancer initiation in the absence of epistasis. Since the driver mutation is deleterious to a cell with only a few passenger mutations, there is a period of stasis in the number of cells until a clone of cells with enough passenger mutations emerges. Only when the driver mutation occurs in one of those cells, the cell population starts to grow rapidly.
No significantly increased frequency of the inversion polymorphism at the WBS-critical region 7q11.23 in German parents of patients with Williams-Beuren syndrome as compared to a population control
Judith Frohnauer, Almuth Caliebe, Stefan Gesk, Carl-Joachim Partsch, Reiner Siebert, Rainer Pankau, Jutta Jenderny
Molecular Cytogenetics , 2010, DOI: 10.1186/1755-8166-3-21
Abstract: FISH analysis was carried out on couples with a child affected by WBS as compared to a population sample composed of different normal individuals: Control group I: couples with two healthy children, control group II: couples with fertility problems, planning ICSI and control group III: couples with two healthy children and one child with a chromosome aberration, not involving region 7q11.23. The three color FISH assay showed that the frequency of the paracentric inversion polymorphism at 7q11.23 in couples with a child affected by WBS was 20.8% (5 out of 24 pairs) as compared to 8.3% (2 out of 24 pairs, control group I), 25% (4 out of 16 pairs, control group II) and 9.1% (1 out of 11 pairs, control group III), respectively (total 7 out of 51 pairs, 13.8%). The frequencies differed between the groups, but this was statistically not significant (p > 0.05, Fisher's test).Our results do not support the hypothesis that the paracentric inversion polymorphism at 7q11.23 is a major predisposing factor for the WBS deletion.Williams-Beuren syndrome (WBS) is a developmental disorder with multisystemic manifestations mainly characterized by vascular stenoses (predominantly supravalvular aortic stenosis (SVAS)), distinctive craniofacial features, mental retardation with a characteristic neurocognitive profile, short stature and some endocrine and connective tissue abnormalities. The WBS syndrome is caused by a heterozygous deletion of contiguous genes at chromosomal region 7q11.23. The common deletions in WBS patients span a genomic region of ~1.5 - ~1.8 mega base pairs (Mb), encompassing approximately 28 genes [1,2].The majority of WBS cases occur sporadically with an estimated prevalence of the disorder as high as 1/7500 newborns [3]. Few cases of autosomal dominant inheritance have been reported. In these families the disease transmitting progenitors usually presented a relatively mild phenotype [4-7].Previous data demonstrated the existence of the paracentric inversion polym
Deep Bisulfite Sequencing of Aberrantly Methylated Loci in a Patient with Multiple Methylation Defects
Jasmin Beygo, Ole Ammerpohl, Daniela Gritzan, Melanie Heitmann, Katrin Rademacher, Julia Richter, Almuth Caliebe, Reiner Siebert, Bernhard Horsthemke, Karin Buiting
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0076953
Abstract: NLRP7 is a maternal effect gene as maternal mutations in this gene cause recurrent hydatidiform moles, spontaneous abortions and stillbirths, whereas live births are very rare. We have studied a patient with multiple anomalies born to a mother with a heterozygous NLRP7 mutation. By array-based CpG methylation analysis of blood DNA from the patient, his parents and 18 normal controls on Illumina Infinium HumanMethylation27 BeadChips we found that the patient had methylation changes (delta ? ≥ 0.3) at many imprinted loci as well as at 87 CpGs associated with 85 genes of unknown imprinting status. Using a pseudoproband (permutation) approach, we found methylation changes at only 7-24 CpGs (mean 15; standard deviation 4.84) in the controls. Thus, the number of abberantly methylated CpGs in the patient is more than 14 standard deviations higher. In order to identify novel imprinted genes among the 85 conspicuous genes in the patient, we selected 19 (mainly hypomethylated) genes for deep bisulfite amplicon sequencing on the ROCHE/454 Genome Sequencer in the patient and at least two additional controls. These controls had not been included in the array analysis and were heterozygous for a single nucleotide polymorphism at the test locus, so that allele-specific DNA methylation patterns could be determined. Apart from FAM50B, which we proved to be imprinted in blood, we did not observe allele-specific DNA methylation at the other 18 loci. We conclude that the patient does not only have methylation defects at imprinted loci but (at least in blood) also an excess of methylation changes at apparently non-imprinted loci.
The Human Retinoblastoma Gene Is Imprinted
Deniz Kanber equal contributor,Tea Berulava equal contributor,Ole Ammerpohl,Diana Mitter,Julia Richter,Reiner Siebert,Bernhard Horsthemke ,Dietmar Lohmann,Karin Buiting
PLOS Genetics , 2009, DOI: 10.1371/journal.pgen.1000790
Abstract: Genomic imprinting is an epigenetic process leading to parent-of-origin–specific DNA methylation and gene expression. To date, ~60 imprinted human genes are known. Based on genome-wide methylation analysis of a patient with multiple imprinting defects, we have identified a differentially methylated CpG island in intron 2 of the retinoblastoma (RB1) gene on chromosome 13. The CpG island is part of a 5′-truncated, processed pseudogene derived from the KIAA0649 gene on chromosome 9 and corresponds to two small CpG islands in the open reading frame of the ancestral gene. It is methylated on the maternal chromosome 13 and acts as a weak promoter for an alternative RB1 transcript on the paternal chromosome 13. In four other KIAA0649 pseudogene copies, which are located on chromosome 22, the two CpG islands have deteriorated and the CpG dinucleotides are fully methylated. By analysing allelic RB1 transcript levels in blood cells, as well as in hypermethylated and 5-aza-2′-deoxycytidine–treated lymphoblastoid cells, we have found that differential methylation of the CpG island skews RB1 gene expression in favor of the maternal allele. Thus, RB1 is imprinted in the same direction as CDKN1C, which operates upstream of RB1. The imprinting of two components of the same pathway indicates that there has been strong evolutionary selection for maternal inhibition of cell proliferation.
DNA-Methylation Profiling of Fetal Tissues Reveals Marked Epigenetic Differences between Chorionic and Amniotic Samples
Christel Eckmann-Scholz, Susanne Bens, Julia Kolarova, Sina Schneppenheim, Almuth Caliebe, Simone Heidemann, Constantin von Kaisenberg, Monika Kautza, Walter Jonat, Reiner Siebert, Ole Ammerpohl
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0039014
Abstract: Epigenetic mechanisms including DNA methylation are supposed to play a key role in fetal development. Here we have investigated fetal DNA-methylation levels of 27,578 CpG loci in 47 chorionic villi (CVS) and 16 amniotic cell (AC) samples. Methylation levels differed significantly between karyotypically normal AC and CVS for 2,014 genes. AC showed more extreme DNA-methylation levels of these genes than CVS and the differentially methylated genes are significantly enriched for processes characteristic for the different cell types sampled. Furthermore, we identified 404 genes differentially methylated in CVS with trisomy 21. These genes were significantly enriched for high CG dinucleotid (CpG) content and developmental processes associated with Down syndrome. Our study points to major tissue-specific differences of fetal DNA-methylation and gives rise to the hypothesis that part of the Down syndrome phenotype is epigenetically programmed in the first trimester of pregnancy.
Inhibition of Anaplastic Lymphoma Kinase (ALK) Activity Provides a Therapeutic Approach for CLTC-ALK-Positive Human Diffuse Large B Cell Lymphomas
Leandro Cerchietti,Christine Damm-Welk,Inga Vater,Wolfram Klapper,Lana Harder,Christiane Pott,Shao Ning Yang,Alfred Reiter,Reiner Siebert,Ari Melnick,Willi Woessmann
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0018436
Abstract: ALK positive diffuse large B-cell lymphomas (DLBCL) are a distinct lymphoma subtype associated with a poor outcome. Most of them feature a t(2;17) encoding a clathrin (CLTC)-ALK fusion protein. The contribution of deregulated ALK-activity in the pathogenesis and maintenance of these DLBCLs is not yet known. We established and characterized the first CLTC-ALK positive DLBCL cell line (LM1). LM1 formed tumors in NOD-SCID mice. The selective ALK inhibitor NVP-TAE684 inhibited growth of LM1 cells in vitro at nanomolar concentrations. NVP-TAE684 repressed ALK-activated signalling pathways and induced apoptosis of LM1 DLBCL cells. Inhibition of ALK-activity resulted in sustained tumor regression in the xenotransplant tumor model. These data indicate a role of CLTC-ALK in the maintenance of the malignant phenotype thereby providing a rationale therapeutic target for these otherwise refractory tumors.
Epigenetic regulation of CD44 in Hodgkin and non-Hodgkin lymphoma
Sonja Eberth, Bj?rn Schneider, Andreas Rosenwald, Elena M Hartmann, Julia Romani, Margarete Zaborski, Reiner Siebert, Hans G Drexler, Hilmar Quentmeier
BMC Cancer , 2010, DOI: 10.1186/1471-2407-10-517
Abstract: We screened for TSG methylation using methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA) in 40 lymphoma-derived cell lines representing anaplastic large cell lymphoma, Burkitt lymphoma (BL), diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), Hodgkin lymphoma and mantle cell lymphoma (MCL) as well as in 50 primary lymphoma samples. The methylation status of differentially methylated CD44 was verified by methylation-specific PCR and bisulfite sequencing. Gene expression of CD44 and its reactivation by DNA demethylation was determined by quantitative real-time PCR and on the protein level by flow cytometry. Induction of apoptosis by anti-CD44 antibody was analyzed by annexin-V/PI staining and flow cytometry.On average 8 ± 2.8 of 24 TSG were methylated per lymphoma cell line and 2.4 ± 2 of 24 TSG in primary lymphomas, whereas 0/24 TSG were methylated in tonsils and blood mononuclear cells from healthy donors. Notably, we identified that CD44 was hypermethylated and transcriptionally silenced in all BL and most FL and DLBCL cell lines, but was usually unmethylated and expressed in MCL cell lines. Concordant results were obtained from primary lymphoma material: CD44 was not methylated in MCL patients (0/11) whereas CD44 was frequently hypermethylated in BL patients (18/29). In cell lines with CD44 hypermethylation, expression was re-inducible at mRNA and protein levels by treatment with the DNA demethylating agent 5-Aza-2'-deoxycytidine, confirming epigenetic regulation of CD44. CD44 ligation assays with a monoclonal anti-CD44 antibody showed that CD44 can mediate apoptosis in CD44+ lymphoma cells. CD44 hypermethylated, CD44- lymphoma cell lines were consistently resistant towards anti-CD44 induced apoptosis.Our data show that CD44 is epigenetically regulated in lymphoma and undergoes de novo methylation in distinct lymphoma subtypes like BL. Thus CD44 may be a promising new epigenetic marker for diagnosis and a potential therape
Array-based DNA methylation profiling of primary lymphomas of the central nervous system
Julia Richter, Ole Ammerpohl, José I Martín-Subero, Manuel Montesinos-Rongen, Marina Bibikova, Eliza Wickham-Garcia, Otmar D Wiestler, Martina Deckert, Reiner Siebert
BMC Cancer , 2009, DOI: 10.1186/1471-2407-9-455
Abstract: Using an array-based technology we have assessed the DNA methylation status of 1,505 individual CpG loci in five PCNSL and compared the results to DNA methylation profiles of 49 DLBCL and ten hematopoietic controls.We identified 194 genes differentially methylated between PCNSL and normal controls. Interestingly, Polycomb target genes and genes with promoters showing a high CpG content were significantly enriched in the group of genes hypermethylated in PCNSL. However, PCNSL and systemic DLBCL did not differ in their methylation pattern.Based on the data presented here, PCNSL and DLBCL do not differ in their DNA methylation pattern. Thus, DNA methylation analysis does not support a separation of PCNSL and DLBCL into individual entities. However, PCNSL and DLBCL differ in their DNA methylation pattern from non- malignant controls.Primary lymphomas of the central nervous system (PCNSL) are highly malignant B-cell lymphomas confined to the central nervous system (CNS) with a poor prognosis [1]. They are considered as separate entity within the updated WHO classification [1], although they cannot be distinguished histologically and immunophenotypically from extracerebral diffuse large B-cell lymphoma (DLBCL). However, based on the remarkably worse clinical course and prognosis it is still a matter of debate whether PCNSL differ from systemic DLBCL with respect to their molecular features and pathogenesis. Interphase cytogenetic and molecular genetic studies have shown that PCNSL share a variety of features with systemic DLBCL. These include rearranged immunoglobulin (IG) gene segments with evidence for ongoing somatic hypermutation, aberrant somatic hypermutation of non-IG genes, translocations affecting the IG and BCL6 genes, gains in chromosome band 18q21, and mutations of the PRDM1 gene [2]. With respect to their gene expression profile PCNSL segregate along the spectrum of systemic DLBCL including the ABC- and GCB-types of DLBCL [3,4].Epigenetic silencing of functio
Conflicting results of prenatal FISH with different probes for Down's Syndrome critical regions associated with mosaicism for a de novo del(21)(q22) characterised by molecular karyotyping: Case report
Christel Eckmann-Scholz, Stefan Gesk, Inga Nagel, Andrea Haake, Susanne Bens, Simone Heidemann, Monika Kautza, Christian Timke, Reiner Siebert, Almuth Caliebe
Molecular Cytogenetics , 2010, DOI: 10.1186/1755-8166-3-16
Abstract: Fluorescence in situ hybridisation (FISH) on uncultured amniotic fluid cells is a widely used means for the rapid prenatal diagnosis of common aneuploidies. Different commercial suppliers provide FISH assays for the detection of trisomies involving the Down syndrome critical regions (DSCR) in 21q22 which have been extensively validated in single institution series [1,2] and multicenter trials [3]. Interpretation of FISH results may be difficult if unexpected results are detected which for example can be caused by structural aberrations or mosaicism. Here we present a case in which rapid FISH screening with different commercial probes for the Down's syndrome critical regions yielded conflicting results with regard to a partial monosomy 21q. Moreover, by extensive conventional and molecular karyotyping we show this diagnostic problem to be caused by a de novo del(21)(q22) as part of a mosaic karyotype. Deletion of 21q is a rare chromosome disorder. In a recent review of 23 patients of whom reliable mapping data are available the variable phenotype depending on the deleted region became obvious [4]. Intrauterine growth retardation which was the initial presentation of the proband seems to be a constant finding.A 35-year-old woman presented at 24+0 weeks of gestation of her fourth pregnancy. She had suffered two early pregnancy losses. The third pregnancy ended in the delivery of a healthy boy. Medical and family history of the proposita and her partner were unremarkable. First trimester-screening including ultrasound and maternal serum biochemistry had been normal (adjusted risks +21 = 1:1839; +18 = 1:610; +13 = 1:3515). In the 25th week, ultrasound revealed symmetric foetal retardation with cerebral ventriculomegaly, partial agenesis of the corpus callosum, short nasal bone and hyperechogenic bowel. Therefore, amniocentesis was performed and foetal karyotyping initiated. For rapid screening for aneuploidies, FISH was performed according to standard methods on uncultur
Hodgkin-Reed-Sternberg Cells in Classical Hodgkin Lymphoma Show Alterations of Genes Encoding the NADPH Oxidase Complex and Impaired Reactive Oxygen Species Synthesis Capacity
Maciej Giefing, Supandi Winoto-Morbach, Justyna Sosna, Claudia D?ring, Wolfram Klapper, Ralf Küppers, Sebastian B?ttcher, Dieter Adam, Reiner Siebert, Stefan Schütze
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0084928
Abstract: The membrane bound NADPH oxidase involved in the synthesis of reactive oxygen species (ROS) is a multi-protein enzyme encoded by CYBA, CYBB, NCF1, NCF2 and NCF4 genes. Growing evidence suggests a role of ROS in the modulation of signaling pathways of non-phagocytic cells, including differentiation and proliferation of B-cell progenitors. Transcriptional downregulation of the CYBB gene has been previously reported in cell lines of the B-cell derived classical Hodgkin lymphoma (cHL). Thus, we explored functional consequences of CYBB downregulation on the NADPH complex. Using flow cytometry to detect and quantify superoxide anion synthesis in cHL cell lines we identified recurrent loss of superoxide anion production in all stimulated cHL cell lines in contrast to stimulated non-Hodgkin lymphoma cell lines. As CYBB loss proved to exert a deleterious effect on the NADPH oxidase complex in cHL cell lines, we analyzed the CYBB locus in Hodgkin and Reed-Sternberg (HRS) cells of primary cHL biopsies by in situ hybridisation and identified recurrent deletions of the gene in 8/18 cases. Immunohistochemical analysis to 14 of these cases revealed a complete lack of detectable CYBB protein expression in all HRS cells in all cases studied. Moreover, by microarray profiling of cHL cell lines we identified additional alterations of NADPH oxidase genes including CYBA copy number loss in 3/7 cell lines and a significant downregulation of the NCF1 transcription (p=0.006) compared to normal B-cell subsets. Besides, NCF1 protein was significantly downregulated (p<0.005) in cHL compared to other lymphoma cell lines. Together this findings show recurrent alterations of the NADPH oxidase encoding genes that result in functional inactivation of the enzyme and reduced production of superoxide anion in cHL.
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