5 results on '"Toprak, Umut H."'
Search Results
2. Mutational patterns and regulatory networks in epigenetic subgroups of meningioma.
- Author
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Paramasivam, Nagarajan, Hübschmann, Daniel, Toprak, Umut H, Ishaque, Naveed, Neidert, Marian, Schrimpf, Daniel, Stichel, Damian, Reuss, David, Sievers, Philipp, Reinhardt, Annekathrin, Wefers, Annika K., Jones, David T. W., Gu, Zuguang, Werner, Johannes, Uhrig, Sebastian, Wirsching, Hans-Georg, Schick, Matthias, Bewerunge-Hudler, Melanie, Beck, Katja, and Brehmer, Stephanie
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HOMEOBOX genes , *GENE enhancers , *GENETIC regulation , *DNA methylation , *NUCLEOTIDE sequence , *NUCLEOTIDE sequencing - Abstract
DNA methylation patterns delineate clinically relevant subgroups of meningioma. We previously established the six meningioma methylation classes (MC) benign 1–3, intermediate A and B, and malignant. Here, we set out to identify subgroup-specific mutational patterns and gene regulation. Whole genome sequencing was performed on 62 samples across all MCs and WHO grades from 62 patients with matched blood control, including 40 sporadic meningiomas and 22 meningiomas arising after radiation (Mrad). RNA sequencing was added for 18 of these cases and chromatin-immunoprecipitation for histone H3 lysine 27 acetylation (H3K27ac) followed by sequencing (ChIP-seq) for 16 samples. Besides the known mutations in meningioma, structural variants were found as the mechanism of NF2 inactivation in a small subset (5%) of sporadic meningiomas, similar to previous reports for Mrad. Aberrations of DMD were found to be enriched in MCs with NF2 mutations, and DMD was among the most differentially upregulated genes in NF2 mutant compared to NF2 wild-type cases. The mutational signature AC3, which has been associated with defects in homologous recombination repair (HRR), was detected in both sporadic meningioma and Mrad, but widely distributed across the genome in sporadic cases and enriched near genomic breakpoints in Mrad. Compared to the other MCs, the number of single nucleotide variants matching the AC3 pattern was significantly higher in the malignant MC, which also exhibited higher genomic instability, determined by the numbers of both large segments affected by copy number alterations and breakpoints between large segments. ChIP-seq analysis for H3K27ac revealed a specific activation of genes regulated by the transcription factor FOXM1 in the malignant MC. This analysis also revealed a super enhancer near the HOXD gene cluster in this MC, which, together with general upregulation of HOX genes in the malignant MC, indicates a role of HOX genes in meningioma aggressiveness. This data elucidates the biological mechanisms rendering different epigenetic subgroups of meningiomas, and suggests leveraging HRR as a novel therapeutic target. [ABSTRACT FROM AUTHOR]
- Published
- 2019
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3. New Brain Tumor Entities Emerge from Molecular Classification of CNS-PNETs.
- Author
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Sturm, Dominik, Orr, Brent A., Toprak, Umut H., Hovestadt, Volker, Jones, David T.W., Capper, David, Sill, Martin, Buchhalter, Ivo, Northcott, Paul A., Leis, Irina, Ryzhova, Marina, Koelsche, Christian, Pfaff, Elke, Allen, Sariah J., Balasubramanian, Gnanaprakash, Worst, Barbara C., Pajtler, Kristian W., Brabetz, Sebastian, Johann, Pascal D., and Sahm, Felix
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BRAIN tumors , *NEUROECTODERMAL tumors , *EMBRYONAL tumors , *AGE factors in disease , *CLINICAL trials , *FORKHEAD transcription factors , *THERAPEUTICS - Abstract
Summary Primitive neuroectodermal tumors of the central nervous system (CNS-PNETs) are highly aggressive, poorly differentiated embryonal tumors occurring predominantly in young children but also affecting adolescents and adults. Herein, we demonstrate that a significant proportion of institutionally diagnosed CNS-PNETs display molecular profiles indistinguishable from those of various other well-defined CNS tumor entities, facilitating diagnosis and appropriate therapy for patients with these tumors. From the remaining fraction of CNS-PNETs, we identify four new CNS tumor entities, each associated with a recurrent genetic alteration and distinct histopathological and clinical features. These new molecular entities, designated “CNS neuroblastoma with FOXR2 activation (CNS NB- FOXR2 ),” “CNS Ewing sarcoma family tumor with CIC alteration (CNS EFT- CIC ),” “CNS high-grade neuroepithelial tumor with MN1 alteration (CNS HGNET- MN1 ),” and “CNS high-grade neuroepithelial tumor with BCOR alteration (CNS HGNET- BCOR ),” will enable meaningful clinical trials and the development of therapeutic strategies for patients affected by poorly differentiated CNS tumors. [ABSTRACT FROM AUTHOR]
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- 2016
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4. IG-MYC+ neoplasms with precursor B-cell phenotype are molecularly distinct from Burkitt lymphomas.
- Author
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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
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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]
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- 2018
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5. Screening drug effects in patient-derived cancer cells links organoid responses to genome alterations.
- Author
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Jabs, Julia, Zickgraf, Franziska M, Park, Jeongbin, Wagner, Steve, Jiang, Xiaoqi, Jechow, Katharina, Kleinheinz, Kortine, Toprak, Umut H, Schneider, Marc A, Meister, Michael, Spaich, Saskia, Sütterlin, Marc, Schlesner, Matthias, Trumpp, Andreas, Sprick, Martin, Eils, Roland, and Conrad, Christian
- Abstract
Cancer drug screening in patient‐derived cells holds great promise for personalized oncology and drug discovery but lacks standardization. Whether cells are cultured as conventional monolayer or advanced, matrix‐dependent organoid cultures influences drug effects and thereby drug selection and clinical success. To precisely compare drug profiles in differently cultured primary cells, we developed DeathPro, an automated microscopy‐based assay to resolve drug‐induced cell death and proliferation inhibition. Using DeathPro, we screened cells from ovarian cancer patients in monolayer or organoid culture with clinically relevant drugs. Drug‐induced growth arrest and efficacy of cytostatic drugs differed between the two culture systems. Interestingly, drug effects in organoids were more diverse and had lower therapeutic potential. Genomic analysis revealed novel links between drug sensitivity and DNA repair deficiency in organoids that were undetectable in monolayers. Thus, our results highlight the dependency of cytostatic drugs and pharmacogenomic associations on culture systems, and guide culture selection for drug tests. [ABSTRACT FROM AUTHOR]
- Published
- 2017
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