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3. Rhabdoid tumors in patients conceived following ART: is there an association?

Author

Nemes, Karolina, primary, Benesch, Martin, additional, Kolarova, Julia, additional, Johann, Pascal, additional, Hasselblatt, Martin, additional, Thomas, Christian, additional, Bens, Susanne, additional, Glaser, Selina, additional, Ammerpohl, Ole, additional, Liaugaudiene, Olga, additional, Sadeghipour, Alireza, additional, von der Weid, Nicolas, additional, Schmid, Irene, additional, Gidding, Corrie, additional, Erdreich-Epstein, Anat, additional, Khurana, Claudia, additional, Ebetsberger-Dachs, Georg, additional, Lemmer, Andreas, additional, Khatib, Ziad, additional, Hernández Marqués, Carmen, additional, Pears, Jane, additional, Quehenberger, Franz, additional, Kordes, Uwe, additional, Vokuhl, Christian, additional, Gerss, Joachim, additional, Schwarz, Heike, additional, Bison, Brigitte, additional, Biegel, Jaclyn A, additional, Siebert, Reiner, additional, and Frühwald, Michael C, additional

Published
2023
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8. Molecular characterization of an embryonal rhabdomyosarcoma occurring in a patient with Kabuki syndrome: report and literature review in the light of tumor predisposition syndromes

Author

Aukema, Sietse M., primary, Glaser, Selina, additional, van den Hout, Mari F. C. M., additional, Dahlum, Sonja, additional, Blok, Marinus J., additional, Hillmer, Morten, additional, Kolarova, Julia, additional, Sciot, Raf, additional, Schott, Dina A., additional, Siebert, Reiner, additional, and Stumpel, Constance T. R. M., additional

Published
2022
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12. IG-MYC+ neoplasms with precursor B-cell phenotype are molecularly distinct from Burkitt lymphomas

Author

Wagener, Rabea, López, Cristina, Kleinheinz, Kortine, Bausinger, Julia, Aukema, Sietse M., Nagel, Inga, Toprak, Umut H., Seufert, Julian, Altmüller, Janine, Thiele, Holger, Schneider, Christof, Kolarova, Julia, Park, Jeongbin, Hübschmann, Daniel, Murga Penas, Eva M., Drexler, Hans G., Attarbaschi, Andishe, Hovland, Randi, Kjeldsen, Eigil, Kneba, Michael, Kontny, Udo, de Leval, Laurence, Nürnberg, Peter, Oschlies, Ilske, Oscier, David, Schlegelberger, Brigitte, Stilgenbauer, Stephan, Wössmann, Wilhelm, Schlesner, Matthias, Burkhardt, Birgit, Klapper, Wolfram, Jaffe, Elaine S., Küppers, Ralf, and Siebert, Reiner

Published
2018
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13. Maternal variants in NLRP and other maternal effect proteins are associated with multilocus imprinting disturbance in offspring

Author

Begemann, Matthias, Rezwan, Faisal I., Beygo, Jasmin, Docherty, Louise E., Kolarova, Julia, Schroeder, Christopher, Buiting, Karin, Chokkalingam, Kamal, Degenhardt, Franziska, Wakeling, Emma L., Kleinle, Stephanie, González Fassrainer, Daniela, Oehl-Jaschkowitz, Barbara, Turner, Claire L. S., Patalan, Michal, Gizewska, Maria, Binder, Gerhard, Bich Ngoc, Can Thi, Chi Dung, Vu, Mehta, Sarju G., Baynam, Gareth, Hamilton-Shield, Julian P., Aljareh, Sara, Lokulo-Sodipe, Oluwakemi, Horton, Rachel, Siebert, Reiner, Elbracht, Miriam, Temple, Isabel Karen, Eggermann, Thomas, and Mackay, Deborah J. G.

Subjects
Beckwith-Wiedemann Syndrome, Medizin, multi-locus imprinting disorder, NLRP5, Infant, Newborn, Diseases, NLRP7, NLRP2, Genomic Imprinting, Protein-Arginine Deiminase Type 6, Pregnancy, Humans, Germ-Line Mutation, Adaptor Proteins, Signal Transducing, PADI6, Chromosomes, Human, Pair 11, Infant, Newborn, DNA Methylation, Pedigree, genomic imprinting, Silver-Russell Syndrome, Protein-Arginine Deiminases, Beckwith-Wiedemann syndrome, Epigenetics, Female, Maternal Inheritance, Silver-Russell syndrome, Apoptosis Regulatory Proteins
Abstract

Journal of medical genetics 55(7), 497-504 (2018). doi:10.1136/jmedgenet-2017-105190, Published by BMJ Publishing Group, London

Published
2018

14. IG‐MYC ‐positive leukemia and lymphoma with precursor B‐cell phenotype are genetically and epigenetically distinct from Burkitt lymphomas

Author

Lopez, Cristina, Wagener, Rabea, Kleinheinz, Kortine, Bausinger, Julia, Aukema, Sietse M., Nagel, Inga, Toprak, Umut H., Seufert, Julian, Altmueller, Janine, Thiele, Holger, Schneider, Christof, Kolarova, Julia, Park, Jeongbin, Hübschmann, Daniel, Penas, Eva M. Murga, Drexler, Hans G., Attarbaschi, Andishe, Hovland, Randi, Kjeldsen, Eigil, Kneba, Michael, Kontny, Udo, de Leval, Laurence, Nürnberg, Peter, Oschlies, Ilske, Oscier, David, Schlegelberger, Brigitte, Stilgenbauer, Stephan, Wössmann, Wilhelm, Schlesner, Matthias, Burkhardt, Birgit, Klapper, Wolfram, Jaffe, Elaine S., Küppers, Ralf, and Siebert, Reiner

Subjects
Medizin
Published
2018

15. Additional file 1: of Aberrant DNA methylation of ADAMTS16 in colorectal and other epithelial cancers

Author

Kordowski, Felix, Kolarova, Julia, Schafmayer, Clemens, Buch, Stephan, Goldmann, Torsten, Marwitz, Sebastian, Kugler, Christian, Scheufele, Swetlana, Gassling, Volker, Németh, Christopher, Brosch, Mario, Hampe, Jochen, Lucius, Ralph, Röder, Christian, Kalthoff, Holger, Siebert, Reiner, Ammerpohl, Ole, and Reiss, Karina

Abstract

Figure S1. Differentially methylated CpGs in tumor tissue compared to non-tumor tissue in CRC patients. Tumor resectats (canc) and peri-tumoral non-malignant resectats (ctrl) from the same patient were analyzed with the HumanMethylation450 BeadChip Array for the methylation of 450 k CpG sites. 72 of 1145 CpGs located in ADAM/TS genes were differentially methylated. The depicted β-value represents a quantitation of the methylation level of the respective CpG-locus. Data were statistically analyzed with Wilcoxon signed-rank and corrected for multiple testing with Benjamini-Hochberg method (**** P

Published
2018
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16. IG-MYC plus neoplasms with precursor B-cell phenotype are molecularly distinct from Burkitt lymphomas

Author

Wagener, Rabea, Lopez, Cristina, Kleinheinz, Kortine, Bausinger, Julia, Aukema, Sietse M., Nagel, Inga, Toprak, Umut H., Seufert, Julian, Altmueller, Janine, Thiele, Holger, Schneider, Christof, Kolarova, Julia, Park, Jeongbin, Huebschmann, Daniel, Penas, Eva M. Murga, Drexler, Hans G., Attarbaschi, Andishe, Hovland, Randi, Kjeldsen, Eigil, Kneba, Michael, Kontny, Udo, de Leval, Laurence, Nuernberg, Peter, Oschlies, Ilske, Oscier, David, Schlegelberger, Brigitte, Stilgenbauer, Stephan, Woessmann, Wilhelm, Schlesner, Matthias, Burkhardt, Birgit, Klapper, Wolfram, Jaffe, Elaine S., Kueppers, Ralf, Siebert, Reiner, Wagener, Rabea, Lopez, Cristina, Kleinheinz, Kortine, Bausinger, Julia, Aukema, Sietse M., Nagel, Inga, Toprak, Umut H., Seufert, Julian, Altmueller, Janine, Thiele, Holger, Schneider, Christof, Kolarova, Julia, Park, Jeongbin, Huebschmann, Daniel, Penas, Eva M. Murga, Drexler, Hans G., Attarbaschi, Andishe, Hovland, Randi, Kjeldsen, Eigil, Kneba, Michael, Kontny, Udo, de Leval, Laurence, Nuernberg, Peter, Oschlies, Ilske, Oscier, David, Schlegelberger, Brigitte, Stilgenbauer, Stephan, Woessmann, Wilhelm, Schlesner, Matthias, Burkhardt, Birgit, Klapper, Wolfram, Jaffe, Elaine S., Kueppers, Ralf, and Siebert, Reiner

Abstract

The WHO Classification of Tumours of Haematopoietic and Lymphoid Tissue notes instances of Burkitt lymphoma/leukemia (BL) with IG-MYC rearrangement displaying a B-cell precursor immunophenotype (termed herein preBLL). To characterize the molecular pathogenesis of preBLL, we investigated 13 preBLL cases (including 1 cell line), of which 12 were analyzable using genome, exome, and targeted sequencing, imbalance mapping, and DNA methylation profiling. In 5 patients with reads across the IG-MYC breakpoint junctions, we found evidence that the translocation derived from an aberrant VDJ recombination, as is typical for IG translocations arising in B-cell precursors. Genomic changes like biallelic IGH translocations or VDJ rearrangements combined with translocation into the VDJ region on the second allele, potentially preventing expression of a productive immunoglobulin, were detected in 6 of 13 cases. We did not detect mutations in genes frequently altered in BL, but instead found activating NRAS and/or KRAS mutations in 7 of 12 preBLLs. Gains on 1q, recurrent in BL and preB lymphoblastic leukemia/lymphoma (pB-ALL/LBL), were detected in 7 of 12 preBLLs. DNA methylation profiling showed preBLL to cluster with precursor B cells and pB-ALL/LBL, but apart from BL. We conclude that preBLL genetically and epigenetically resembles pB-ALL/LBL rather than BL. Therefore, we propose that preBLL be considered as a pB-ALL/LBL with recurrent genetic abnormalities.

Published
2018

17. Additional file 2: of Mosaic genome-wide maternal isodiploidy: an extreme form of imprinting disorder presenting as prenatal diagnostic challenge

Author

Bens, Susanne, Luedeke, Manuel, Richter, Tanja, Graf, Melanie, Kolarova, Julia, Barbi, Gotthold, Krisztian Lato, Barth, Thomas, and Siebert, Reiner

Subjects
fungi
Abstract

Results from quantitative fluorescence-polymerase chain reaction (QF-PCR) for chromosomes 13, 18, 21, X, and Y including peak areas and allele ratios. AF: uncultured amniotic fluid cells; AFc: cultured amniotic fluid cells; P: placenta tissue; M: mother, F: father, n.a. not applicable. (PDF 79Â kb)

Published
2017
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18. Additional file 1: of Mosaic genome-wide maternal isodiploidy: an extreme form of imprinting disorder presenting as prenatal diagnostic challenge

Author

Bens, Susanne, Luedeke, Manuel, Richter, Tanja, Graf, Melanie, Kolarova, Julia, Barbi, Gotthold, Krisztian Lato, Barth, Thomas, and Siebert, Reiner

Abstract

Primer sequences applied for quantitative fluorescence-polymerase chain reaction (QF-PCR) for chromosomes 13, 18, 21, X, and Y. F: forward primer; R: reverse primer. (PDF 31Â kb)

Published
2017
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19. Maternal variants in NLRP and other maternal effect proteins are associated with multilocus imprinting disturbance in offspring

Author

Begemann, Matthias, primary, Rezwan, Faisal I, additional, Beygo, Jasmin, additional, Docherty, Louise E, additional, Kolarova, Julia, additional, Schroeder, Christopher, additional, Buiting, Karin, additional, Chokkalingam, Kamal, additional, Degenhardt, Franziska, additional, Wakeling, Emma L, additional, Kleinle, Stephanie, additional, González Fassrainer, Daniela, additional, Oehl-Jaschkowitz, Barbara, additional, Turner, Claire L S, additional, Patalan, Michal, additional, Gizewska, Maria, additional, Binder, Gerhard, additional, Bich Ngoc, Can Thi, additional, Chi Dung, Vu, additional, Mehta, Sarju G, additional, Baynam, Gareth, additional, Hamilton-Shield, Julian P, additional, Aljareh, Sara, additional, Lokulo-Sodipe, Oluwakemi, additional, Horton, Rachel, additional, Siebert, Reiner, additional, Elbracht, Miriam, additional, Temple, Isabel Karen, additional, Eggermann, Thomas, additional, and Mackay, Deborah J G, additional

Published
2018
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21. Charakterisierung der DNA-Methylierung geprägter Gene im Kontext physiologischer und gestörter Entwicklung und somatischer Differenzierung

Author

Kolarova, Julia, Prof. Dr. Manuela Dittmar, Prof. Dr. Reiner Siebert, Dittmar, Manuela, and Siebert, Reiner

Subjects
DNA-Methylierung, doctoral thesis, Abschlussarbeit, DNA-Methylierung, genomische Prägung, Imprinting, ddc:570, Imprinting, ddc:5XX, genomische Prägung, Mathematisch-Naturwissenschaftliche Fakultät, Faculty of Mathematics and Natural Sciences
Abstract

Die Expression von Genen in Abhängigkeit von der elterlichen Herkunft des Allels wird als Imprinting (“Prägung“) bezeichnet. Diese Eltern-spezifische Expression wird u.a. durch die Allel-spezifische DNA-Methylierung differenziell methylierter Regionen (DMRs) reguliert. Dabei liegt eine DMR in der Regel auf einem der beiden elterlichen Allele methyliert und auf dem anderen Allel unmethyliert vor. Da viele geprägte Gene in Wachstums- und Differenzierungsprozesse eingebunden sind, ist die korrekte Regulation der Expression geprägter Gene wichtig für die physiologische Entwicklung. Eine gestörte DNA-Methylierung von DMRs kann die aberrante Expression elterlich geprägter Gene bewirken. Konstitutionelle Störungen der elterlichen Prägung sind sowohl mit klassischen Imprintingsyndromen als auch mit Multi-Locus Methylierungsdefekten (MLMD) assoziiert. DNA-Methylierungsstörungen geprägter Gene werden aber auch bei benignen und malignen somatischen Erkrankungen beschrieben und können zu deren Krankheitsentstehung und Progression beitragen. Ausgangspunkt für die vorliegende Arbeit waren, bis auf die IG-DMR auf Chromosom 14q32.2, sämtliche 34 somatisch und 20 Plazenta-spezifisch geprägten DMRs des Menschen. Da diese DMRs z.T. erst jüngst beschrieben wurden, sind zu vielen keine systematischen DNA-Methylierungsdaten zur physiologischen Entwicklung oder zu pathologischen Prozessen publiziert. Deshalb war das Ziel dieser Arbeit, die physiologische DNA-Methylierung dieser geprägten DMRs in pränatalen und postnatalen Normalgeweben auch unter Berücksichtigung des Einflusses der Gewebefixierung zu charakterisieren. Weiterhin sollte die DNA-Methylierung dieser DMRs im Kontext benigner und maligner somatischer Erkrankungen, konstitutioneller Störungen und in Patienten-spezifischen induzierten pluripotenten Stammzellen (iPSZ) analysiert werden... The term parental imprinting describes the expression of genes dependend of the parental origin of the alleles. This parental-specific expression is regulated amongst others by allele-specific DNA-methylation of differentially methylated regions (DMRs). In general, the DMR on one of the two parental alleles is methylated while the other is unmethylated. Due to the involvement of imprinted genes in growth and differentiation processes the accurate regulation of imprinted gene expression is important for the physiological development. A disturbed DNA-methylation at a DMR can cause the aberrant expression of parent-specific imprinted genes. Constitutional disturbances of the parental imprinting are associated with classical imprinting disorders as well as with multi locus methylation defects (MLMD). Moreover, aberrant DNA-methylation of imprinted genes has also been described in benign and malignant somatic diseases and may contribute to their development and progression. All 34 somatic, except for the somatic IG-DMR on chromosome 14q32.2, and 20 placental-specific human imprinted genes were analysed in this study. Since these DMRs have been described just recently DNA-methylation data concerning the physiological development or regarding pathological processes have yet not been published. Therefore, the aim of this study was to characterize the physiological DNA-methylation of these imprinted DMRs in prenatal and postnatal normal tissues. Moreover, the influence of tissue fixation on DNA-methylation should be studied. Furthermore, the DNA-methylation of these DMRs should be analysed in context of benign and malignant somatic diseases, constitutional disorders and in patient-specific induced pluripotent stem cells (iPSC)...

Published
2015

22. DNA Methylation Analysis in Nonalcoholic Fatty Liver Disease Suggests Distinct Disease-Specific and Remodeling Signatures after Bariatric Surgery

Author

Ahrens, Markus, Ammerpohl, Ole, von Schönfels, Witigo, Kolarova, Julia, Bens, Susanne, Itzel, Timo, Teufel, Andreas, Herrmann, Alexander, Brosch, Mario, Hinrichsen, Holger, Erhart, Wiebke, Egberts, Jan, Sipos, Bence, Schreiber, Stefan, Häsler, Robert, Stickel, Felix, Becker, Thomas, Krawczak, Michael, Röcken, Christoph, Siebert, Reiner, Schafmayer, Clemens, and Hampe, Jochen

Published
2013
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24. Phenotypic Spectrum and Extent of DNA Methylation Defects Associated with Multilocus Imprinting Disturbances

Author

Bens, Susanne, primary, Kolarova, Julia, additional, Beygo, Jasmin, additional, Buiting, Karin, additional, Caliebe, Almuth, additional, Eggermann, Thomas, additional, Gillessen-Kaesbach, Gabriele, additional, Prawitt, Dirk, additional, Thiele-Schmitz, Susanne, additional, Begemann, Matthias, additional, Enklaar, Thorsten, additional, Gutwein, Jana, additional, Haake, Andrea, additional, Paul, Ulrike, additional, Richter, Julia, additional, Soellner, Lukas, additional, Vater, Inga, additional, Monk, David, additional, Horsthemke, Bernhard, additional, Ammerpohl, Ole, additional, and Siebert, Reiner, additional

Published
2016
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30. IG-MYC+neoplasms with precursor B-cell phenotype are molecularly distinct from Burkitt lymphomas

Author

Wagener, Rabea, López, Cristina, Kleinheinz, Kortine, Bausinger, Julia, Aukema, Sietse M., Nagel, Inga, Toprak, Umut H., Seufert, Julian, Altmüller, Janine, Thiele, Holger, Schneider, Christof, Kolarova, Julia, Park, Jeongbin, Hübschmann, Daniel, Murga Penas, Eva M., Drexler, Hans G., Attarbaschi, Andishe, Hovland, Randi, Kjeldsen, Eigil, Kneba, Michael, Kontny, Udo, de Leval, Laurence, Nürnberg, Peter, Oschlies, Ilske, Oscier, David, Schlegelberger, Brigitte, Stilgenbauer, Stephan, Wössmann, Wilhelm, Schlesner, Matthias, Burkhardt, Birgit, Klapper, Wolfram, Jaffe, Elaine S., Küppers, Ralf, and Siebert, Reiner

Abstract

The WHO Classification of Tumours of Haematopoietic and Lymphoid Tissuenotes instances of Burkitt lymphoma/leukemia (BL) with IG-MYCrearrangement displaying a B-cell precursor immunophenotype (termed herein “preBLL”). To characterize the molecular pathogenesis of preBLL, we investigated 13 preBLL cases (including 1 cell line), of which 12 were analyzable using genome, exome, and targeted sequencing, imbalance mapping, and DNA methylation profiling. In 5 patients with reads across the IG-MYCbreakpoint junctions, we found evidence that the translocation derived from an aberrant VDJ recombination, as is typical for IG translocations arising in B-cell precursors. Genomic changes like biallelic IGH translocations or VDJ rearrangements combined with translocation into the VDJ region on the second allele, potentially preventing expression of a productive immunoglobulin, were detected in 6 of 13 cases. We did not detect mutations in genes frequently altered in BL, but instead found activating NRASand/or KRASmutations in 7 of 12 preBLLs. Gains on 1q, recurrent in BL and preB lymphoblastic leukemia/lymphoma (pB-ALL/LBL), were detected in 7 of 12 preBLLs. DNA methylation profiling showed preBLL to cluster with precursor B cells and pB-ALL/LBL, but apart from BL. We conclude that preBLL genetically and epigenetically resembles pB-ALL/LBL rather than BL. Therefore, we propose that preBLL be considered as a pB-ALL/LBL with recurrent genetic abnormalities.

Published
2018
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31. Maternal variants in NLRPand other maternal effect proteins are associated with multilocus imprinting disturbance in offspring

Author

Begemann, Matthias, Rezwan, Faisal I, Beygo, Jasmin, Docherty, Louise E, Kolarova, Julia, Schroeder, Christopher, Buiting, Karin, Chokkalingam, Kamal, Degenhardt, Franziska, Wakeling, Emma L, Kleinle, Stephanie, González Fassrainer, Daniela, Oehl-Jaschkowitz, Barbara, Turner, Claire L S, Patalan, Michal, Gizewska, Maria, Binder, Gerhard, Bich Ngoc, Can Thi, Chi Dung, Vu, Mehta, Sarju G, Baynam, Gareth, Hamilton-Shield, Julian P, Aljareh, Sara, Lokulo-Sodipe, Oluwakemi, Horton, Rachel, Siebert, Reiner, Elbracht, Miriam, Temple, Isabel Karen, Eggermann, Thomas, and Mackay, Deborah J G

Abstract

BackgroundGenomic imprinting results from the resistance of germline epigenetic marks to reprogramming in the early embryo for a small number of mammalian genes. Genetic, epigenetic or environmental insults that prevent imprints from evading reprogramming may result in imprinting disorders, which impact growth, development, behaviour and metabolism. We aimed to identify genetic defects causing imprinting disorders by whole-exome sequencing in families with one or more members affected by multilocus imprinting disturbance.MethodsWhole-exome sequencing was performed in 38 pedigrees where probands had multilocus imprinting disturbance, in five of whom maternal variants in NLRP5have previously been found.ResultsWe now report 15 further pedigrees in which offspring had disturbance of imprinting, while their mothers had rare, predicted-deleterious variants in maternal effect genes, including NLRP2, NLRP7and PADI6. As well as clinical features of well-recognised imprinting disorders, some offspring had additional features including developmental delay, behavioural problems and discordant monozygotic twinning, while some mothers had reproductive problems including pregnancy loss.ConclusionThe identification of 20 putative maternal effect variants in 38 families affected by multilocus imprinting disorders adds to the evidence that maternal genetic factors affect oocyte fitness and thus offspring development. Testing for maternal-effect genetic variants should be considered in families affected by atypical imprinting disorders.

Published
2018
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32. Frequency and characterization of DNA methylation defects in children born SGA

Author

Bens, Susanne, primary, Haake, Andrea, additional, Richter, Julia, additional, Leohold, Judith, additional, Kolarova, Julia, additional, Vater, Inga, additional, Riepe, Felix G, additional, Buiting, Karin, additional, Eggermann, Thomas, additional, Gillessen-Kaesbach, Gabriele, additional, Platzer, Konrad, additional, Prawitt, Dirk, additional, Caliebe, Almuth, additional, and Siebert, Reiner, additional

Published
2012
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33. DNA-Methylation Profiling of Fetal Tissues Reveals Marked Epigenetic Differences between Chorionic and Amniotic Samples

Author

Eckmann-Scholz, Christel, primary, Bens, Susanne, additional, Kolarova, Julia, additional, Schneppenheim, Sina, additional, Caliebe, Almuth, additional, Heidemann, Simone, additional, von Kaisenberg, Constantin, additional, Kautza, Monika, additional, Jonat, Walter, additional, Siebert, Reiner, additional, and Ammerpohl, Ole, additional

Published
2012
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34. Frequency and characterization of DNA methylation defects in children born SGA.

Author

Bens, Susanne, Haake, Andrea, Richter, Julia, Leohold, Judith, Kolarova, Julia, Vater, Inga, Riepe, Felix G, Buiting, Karin, Eggermann, Thomas, Gillessen-Kaesbach, Gabriele, Platzer, Konrad, Prawitt, Dirk, Caliebe, Almuth, and Siebert, Reiner

Subjects
DNA methylation, GESTATIONAL age, GENOMIC imprinting, LOCUS (Genetics), ALLELES, CYTOSINE, NEUROGENETICS
Abstract

Various genes located at imprinted loci and regulated by epigenetic mechanisms are involved in the control of growth and differentiation. The broad phenotypic variability of imprinting disorders suggests that individuals with inborn errors of imprinting might remain undetected among patients born small for gestational age (SGA). We evaluated quantitative DNA methylation analysis at differentially methylated regions (DMRs) of 10 imprinted loci (PLAGL1, IGF2R DMR2, GRB10, H19 DMR, IGF2, MEG3, NDN, SNRPN, NESP, NESPAS) by bisulphite pyrosequencing in 98 patients born SGA and 50 controls. For IGF2R DMR2, methylation patterns of additional 47 parent pairs and one mother (95 individuals) of patients included in the SGA cohort were analyzed. In six out of 98 patients born SGA, we detected DNA methylation changes at single loci. In one child, the diagnosis of upd(14)mat syndrome owing to an epimutation of the MEG3 locus in 14q32 could be established. The remaining five patients showed hypomethylation at GRB10 (n=2), hypomethylation at the H19 3CTCF-binding site (n=1), hypermethylation at NDN (n=1) and hypermethylation at IGF2 (n=1). IGF2R DMR2 hypermethylation was detected in five patients, six parents of patients in the SGA cohort and two controls. We conclude that aberrant methylation at imprinted loci in children born SGA exists but seems to be rare if known imprinting syndromes are excluded. Further investigations on the physiological variations and the functional consequences of the detected aberrant methylation are necessary before final conclusions on the clinical impact can be drawn. [ABSTRACT FROM AUTHOR]

Published
2013
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35. IG-MYC+ neoplasms with precursor B-cell phenotype are molecularly distinct from Burkitt lymphomas.

Author

Wagener, Rabea, López, Cristina, Kleinheinz, Kortine, Bausinger, Julia, Aukema, Sietse M., Nagel, Inga, Toprak, Umut H., Seufert, Julian, Altmüller, Janine, Thiele, Holger, Schneider, Christof, Kolarova, Julia, Park, Jeongbin, Hübschmann, Daniel, Murga Penas, Eva M., Drexler, Hans G., Attarbaschi, Andishe, Hovland, Randi, Kjeldsen, Eigil, and Kneba, Michael

Subjects
*BURKITT'S lymphoma, *LEUKEMIA, *B cells, *PHENOTYPES, *MYC oncogenes, *IMMUNOGLOBULINS, *CHROMOSOMAL rearrangement, *CHROMOSOMAL translocation
Abstract

The WHO Classification of Tumours of Haematopoietic and Lymphoid Tissue notes instances of Burkitt lymphoma/leukemia (BL) with IG-MYC rearrangement displaying a B-cell precursor immunophenotype (termed herein "preBLL"). To characterize the molecular pathogenesis of preBLL, we investigated 13 preBLL cases (including 1 cell line), of which 12 were analyzable using genome, exome, and targeted sequencing, imbalance mapping, and DNA methylation profiling. In 5 patients with reads across the IG-MYC breakpoint junctions, we found evidence that the translocation derived from an aberrant VDJ recombination, as is typical for IG translocations arising in B-cell precursors. Genomic changes like biallelic IGH translocations or VDJ rearrangements combined with translocation into the VDJ region on the second allele, potentially preventing expression of a productive immunoglobulin, were detected in 6 of 13 cases. We did not detect mutations in genes frequently altered in BL, but instead found activating NRAS and/or KRAS mutations in 7 of 12 preBLLs. Gains on 1q, recurrent in BL and preB lymphoblastic leukemia/lymphoma (pB-ALL/LBL), were detected in 7 of 12 preBLLs. DNA methylation profiling showed preBLL to cluster with precursor B cells and pB-ALL/LBL, but apart from BL.Weconclude that preBLL genetically and epigenetically resembles pB-ALL/LBL rather than BL. Therefore,we propose that preBLL be considered as a pB-ALL/LBL with recurrent genetic abnormalities. [ABSTRACT FROM AUTHOR]

Published
2018
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36. Quantitative DNA Methylation Profiling in Cancer.

Author

Ammerpohl O, Haake A, Kolarova J, and Siebert R

Subjects
Base Sequence, DNA analysis, Epigenesis, Genetic, Gene Expression Regulation, Neoplastic, Humans, Neoplasms genetics, Sulfites chemistry, DNA genetics, DNA Fingerprinting methods, DNA Methylation
Abstract

Epigenetic mechanisms including DNA methylation are fundamental for the regulation of gene expression. Epigenetic alterations can lead to the development and the evolution of malignant tumors as well as the emergence of phenotypically different cancer cells or metastasis from one single tumor cell. Here we describe bisulfite pyrosequencing, a technology to perform quantitative DNA methylation analyses, to detect aberrant DNA methylation in malignant tumors.

Published
2016
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37. DNA methylome analysis in Burkitt and follicular lymphomas identifies differentially methylated regions linked to somatic mutation and transcriptional control.

Author

Kretzmer H, Bernhart SH, Wang W, Haake A, Weniger MA, Bergmann AK, Betts MJ, Carrillo-de-Santa-Pau E, Doose G, Gutwein J, Richter J, Hovestadt V, Huang B, Rico D, Jühling F, Kolarova J, Lu Q, Otto C, Wagener R, Arnolds J, Burkhardt B, Claviez A, Drexler HG, Eberth S, Eils R, Flicek P, Haas S, Humme M, Karsch D, Kerstens HHD, Klapper W, Kreuz M, Lawerenz C, Lenzek D, Loeffler M, López C, MacLeod RAF, Martens JHA, Kulis M, Martín-Subero JI, Möller P, Nage I, Picelli S, Vater I, Rohde M, Rosenstiel P, Rosolowski M, Russell RB, Schilhabel M, Schlesner M, Stadler PF, Szczepanowski M, Trümper L, Stunnenberg HG, Küppers R, Ammerpohl O, Lichter P, Siebert R, Hoffmann S, and Radlwimmer B

Subjects
Adolescent, Adult, Aged, B-Lymphocytes metabolism, Cell Line, Tumor, Child, Child, Preschool, Female, Genome, Human genetics, Germinal Center metabolism, High-Throughput Nucleotide Sequencing methods, Humans, Male, Middle Aged, Oncogene Proteins, Fusion genetics, Proto-Oncogene Proteins c-bcl-2 genetics, Proto-Oncogene Proteins c-myc genetics, Signal Transduction genetics, Translocation, Genetic, Young Adult, Burkitt Lymphoma genetics, DNA Methylation, Lymphoma, Follicular genetics, Mutation, Transcriptome genetics
Abstract

Although Burkitt lymphomas and follicular lymphomas both have features of germinal center B cells, they are biologically and clinically quite distinct. Here we performed whole-genome bisulfite, genome and transcriptome sequencing in 13 IG-MYC translocation-positive Burkitt lymphoma, nine BCL2 translocation-positive follicular lymphoma and four normal germinal center B cell samples. Comparison of Burkitt and follicular lymphoma samples showed differential methylation of intragenic regions that strongly correlated with expression of associated genes, for example, genes active in germinal center dark-zone and light-zone B cells. Integrative pathway analyses of regions differentially methylated in Burkitt and follicular lymphomas implicated DNA methylation as cooperating with somatic mutation of sphingosine phosphate signaling, as well as the TCF3-ID3 and SWI/SNF complexes, in a large fraction of Burkitt lymphomas. Taken together, our results demonstrate a tight connection between somatic mutation, DNA methylation and transcriptional control in key B cell pathways deregulated differentially in Burkitt lymphoma and other germinal center B cell lymphomas.

Published
2015
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