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Dive into the research topics where Bernhard Radlwimmer is active.

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Featured researches published by Bernhard Radlwimmer.


Cancer Cell | 2012

Hotspot Mutations in H3F3A and IDH1 Define Distinct Epigenetic and Biological Subgroups of Glioblastoma

Dominik Sturm; Hendrik Witt; Volker Hovestadt; Dong Anh Khuong-Quang; David T. W. Jones; Carolin Konermann; Elke Pfaff; Martje Tönjes; Martin Sill; Sebastian Bender; Marcel Kool; Marc Zapatka; Natalia Becker; Manuela Zucknick; Thomas Hielscher; Xiao Yang Liu; Adam M. Fontebasso; Marina Ryzhova; Steffen Albrecht; Karine Jacob; Marietta Wolter; Martin Ebinger; Martin U. Schuhmann; Timothy Van Meter; Michael C. Frühwald; Holger Hauch; Arnulf Pekrun; Bernhard Radlwimmer; Tim Niehues; Gregor Von Komorowski

Glioblastoma (GBM) is a brain tumor that carries a dismal prognosis and displays considerable heterogeneity. We have recently identified recurrent H3F3A mutations affecting two critical amino acids (K27 and G34) of histone H3.3 in one-third of pediatric GBM. Here, we show that each H3F3A mutation defines an epigenetic subgroup of GBM with a distinct global methylation pattern, and that they are mutually exclusive with IDH1 mutations, which characterize a third mutation-defined subgroup. Three further epigenetic subgroups were enriched for hallmark genetic events of adult GBM and/or established transcriptomic signatures. We also demonstrate that the two H3F3A mutations give rise to GBMs in separate anatomic compartments, with differential regulation of transcription factors OLIG1, OLIG2, and FOXG1, possibly reflecting different cellular origins.


Nature | 2011

An endogenous tumour-promoting ligand of the human aryl hydrocarbon receptor

Christiane A. Opitz; Ulrike Litzenburger; Felix Sahm; Martina Ott; Isabel Tritschler; Saskia Trump; Theresa Schumacher; Leonie Jestaedt; Dieter Schrenk; Michael Weller; Manfred Jugold; Gilles J. Guillemin; Christine L. Miller; Christian Lutz; Bernhard Radlwimmer; Irina Lehmann; Andreas von Deimling; Wolfgang Wick; Michael Platten

Activation of the aryl hydrocarbon receptor (AHR) by environmental xenobiotic toxic chemicals, for instance 2,3,7,8-tetrachlorodibenzo-p-dioxin (dioxin), has been implicated in a variety of cellular processes such as embryogenesis, transformation, tumorigenesis and inflammation. But the identity of an endogenous ligand activating the AHR under physiological conditions in the absence of environmental toxic chemicals is still unknown. Here we identify the tryptophan (Trp) catabolite kynurenine (Kyn) as an endogenous ligand of the human AHR that is constitutively generated by human tumour cells via tryptophan-2,3-dioxygenase (TDO), a liver- and neuron-derived Trp-degrading enzyme not yet implicated in cancer biology. TDO-derived Kyn suppresses antitumour immune responses and promotes tumour-cell survival and motility through the AHR in an autocrine/paracrine fashion. The TDO–AHR pathway is active in human brain tumours and is associated with malignant progression and poor survival. Because Kyn is produced during cancer progression and inflammation in the local microenvironment in amounts sufficient for activating the human AHR, these results provide evidence for a previously unidentified pathophysiological function of the AHR with profound implications for cancer and immune biology.


American Journal of Human Genetics | 2006

A Chromosome 8 Gene-Cluster Polymorphism with Low Human Beta-Defensin 2 Gene Copy Number Predisposes to Crohn Disease of the Colon

Klaus Fellermann; Daniel E. Stange; Elke Schaeffeler; Hartmut Schmalzl; Jan Wehkamp; Charles L. Bevins; Walter Reinisch; Alexander Teml; Matthias Schwab; Peter Lichter; Bernhard Radlwimmer; Eduard F. Stange

Defensins are endogenous antimicrobial peptides that protect the intestinal mucosa against bacterial invasion. It has been suggested that deficient defensin expression may underlie the chronic inflammation of Crohn disease (CD). The DNA copy number of the beta-defensin gene cluster on chromosome 8p23.1 is highly polymorphic within the healthy population, which suggests that the defective beta-defensin induction in colonic CD could be due to low beta-defensin-gene copy number. Here, we tested this hypothesis, using genomewide DNA copy number profiling by array-based comparative genomic hybridization and quantitative polymerase-chain-reaction analysis of the human beta-defensin 2 (HBD-2) gene. We showed that healthy individuals, as well as patients with ulcerative colitis, have a median of 4 (range 2-10) HBD-2 gene copies per genome. In a surgical cohort with ileal or colonic CD and in a second large cohort with inflammatory bowel diseases, those with ileal resections/disease exhibited a normal median HBD-2 copy number of 4, whereas those with colonic CD had a median of only 3 copies per genome (P=.008 for the surgical cohort; P=.032 for the second cohort). Overall, the copy number distribution in colonic CD was shifted to lower numbers compared with controls (P=.002 for both the surgical cohort and the cohort with inflammatory bowel diseases). Individuals with < or = 3 copies have a significantly higher risk of developing colonic CD than did individuals with > or = 4 copies (odds ratio 3.06; 95% confidence interval 1.46-6.45). An HBD-2 gene copy number of < 4 was associated with diminished mucosal HBD-2 mRNA expression (P=.033). In conclusion, a lower HBD-2 gene copy number in the beta-defensin locus predisposes to colonic CD, most likely through diminished beta-defensin expression.


Journal of Clinical Investigation | 2008

BRAF gene duplication constitutes a mechanism of MAPK pathway activation in low-grade astrocytomas

Stefan M. Pfister; Wibke G. Janzarik; Marc Remke; Aurélie Ernst; Wiebke Werft; Natalia Becker; Grischa Toedt; Andrea Wittmann; Christian P. Kratz; Heike Olbrich; Rezvan Ahmadi; Barbara Thieme; Stefan Joos; Bernhard Radlwimmer; Andreas E. Kulozik; Torsten Pietsch; Christel Herold-Mende; Astrid Gnekow; Guido Reifenberger; Andrey Korshunov; Wolfram Scheurlen; Heymut Omran; Peter Lichter

The molecular pathogenesis of pediatric astrocytomas is still poorly understood. To further understand the genetic abnormalities associated with these tumors, we performed a genome-wide analysis of DNA copy number aberrations in pediatric low-grade astrocytomas by using array-based comparative genomic hybridization. Duplication of the BRAF protooncogene was the most frequent genomic aberration, and tumors with BRAF duplication showed significantly increased mRNA levels of BRAF and a downstream target, CCND1, as compared with tumors without duplication. Furthermore, denaturing HPLC showed that activating BRAF mutations were detected in some of the tumors without BRAF duplication. Similarly, a marked proportion of low-grade astrocytomas from adult patients also had BRAF duplication. Both the stable silencing of BRAF through shRNA lentiviral transduction and pharmacological inhibition of MEK1/2, the immediate downstream phosphorylation target of BRAF, blocked the proliferation and arrested the growth of cultured tumor cells derived from low-grade gliomas. Our findings implicate aberrant activation of the MAPK pathway due to gene duplication or mutation of BRAF as a molecular mechanism of pathogenesis in low-grade astrocytomas and suggest inhibition of the MAPK pathway as a potential treatment.


Cancer Cell | 2013

Reduced H3K27me3 and DNA Hypomethylation Are Major Drivers of Gene Expression in K27M Mutant Pediatric High-Grade Gliomas

Sebastian Bender; Yujie Tang; Anders M. Lindroth; Volker Hovestadt; David T. W. Jones; Marcel Kool; Marc Zapatka; Paul A. Northcott; Dominik Sturm; Wei Wang; Bernhard Radlwimmer; Jonas W. Højfeldt; Nathalene Truffaux; David Castel; Simone Schubert; Marina Ryzhova; Huriye Şeker-Cin; Jan Gronych; Pascal-David Johann; Sebastian Stark; Jochen Meyer; Till Milde; Martin U. Schuhmann; Martin Ebinger; Camelia Maria Monoranu; Anitha Ponnuswami; Spenser Chen; Chris Jones; Olaf Witt; V. Peter Collins

Two recurrent mutations, K27M and G34R/V, within histone variant H3.3 were recently identified in ∼50% of pHGGs. Both mutations define clinically and biologically distinct subgroups of pHGGs. Here, we provide further insight about the dominant-negative effect of K27M mutant H3.3, leading to a global reduction of the repressive histone mark H3K27me3. We demonstrate that this is caused by aberrant recruitment of the PRC2 complex to K27M mutant H3.3 and enzymatic inhibition of the H3K27me3-establishing methyltransferase EZH2. By performing chromatin immunoprecipitation followed by next-generation sequencing and whole-genome bisulfite sequencing in primary pHGGs, we show that reduced H3K27me3 levels and DNA hypomethylation act in concert to activate gene expression in K27M mutant pHGGs.


Journal of Clinical Oncology | 2009

Outcome Prediction in Pediatric Medulloblastoma Based on DNA Copy-Number Aberrations of Chromosomes 6q and 17q and the MYC and MYCN Loci

Stefan M. Pfister; Marc Remke; Axel Benner; Frank Mendrzyk; Grischa Toedt; Jörg Felsberg; Andrea Wittmann; Frauke Devens; Nicolas U. Gerber; Stefan Joos; Andreas E. Kulozik; Guido Reifenberger; Stefan Rutkowski; Otmar D. Wiestler; Bernhard Radlwimmer; Wolfram Scheurlen; Peter Lichter; Andrey Korshunov

PURPOSE Medulloblastoma is the most common malignant brain tumor in children. Current treatment decisions are based on clinical variables. Novel tumor-derived biomarkers may improve the risk stratification of medulloblastoma patients. PATIENTS AND METHODS A model for the molecular risk stratification was proposed from an array-based comparative genomic hybridization (array-CGH) screen (n = 80). Fluorescence in situ hybridization (FISH) analyses for chromosome arms 6q, 17p, and 17q and the MYC and MYCN loci were performed in an independent validation set (n = 260). Copy number aberrations were correlated with clinical, histologic, and survival data. RESULTS Gain of 6q and 17q and genomic amplification of MYC or MYCN were each associated with poor outcome in the array-CGH study (n = 80). In contrast, all patients with 6q-deleted tumors survived. Given these findings, the following hierarchical molecular staging system was defined: (1) MYC/MYCN amplification, (2) 6q gain, (3) 17q gain, (4) 6q and 17q balanced, and (5) 6q deletion. The prognostic value of this staging system was investigated by FISH analysis (n = 260). The addition of molecular markers to clinical risk factors resulted in the identification of a large proportion of patients (72 of 260 patients; 30%) at high risk for relapse and death who would be considered standard risk by application of clinical variables alone. CONCLUSION Genomic aberrations in medulloblastoma are powerful independent markers of disease progression and survival. By adding genomic markers to established clinical and histologic variables, outcome prediction can be substantially improved. Because the analyses can be conducted on routine paraffin-embedded material, it will be especially feasible to use this novel molecular staging system in large multicenter clinical trials.


Nature Genetics | 2012

Recurrent mutation of the ID3 gene in Burkitt lymphoma identified by integrated genome, exome and transcriptome sequencing

Julia Richter; Matthias Schlesner; Steve Hoffmann; Markus Kreuz; Ellen Leich; Birgit Burkhardt; Maciej Rosolowski; Ole Ammerpohl; Rabea Wagener; Stephan H. Bernhart; Dido Lenze; Monika Szczepanowski; Maren Paulsen; Simone Lipinski; Robert B. Russell; Sabine Adam-Klages; Gordana Apic; Alexander Claviez; Dirk Hasenclever; Volker Hovestadt; Nadine Hornig; Jan O. Korbel; Dieter Kube; David Langenberger; Chris Lawerenz; Jasmin Lisfeld; Katharina Meyer; Simone Picelli; Jordan Pischimarov; Bernhard Radlwimmer

Burkitt lymphoma is a mature aggressive B-cell lymphoma derived from germinal center B cells. Its cytogenetic hallmark is the Burkitt translocation t(8;14)(q24;q32) and its variants, which juxtapose the MYC oncogene with one of the three immunoglobulin loci. Consequently, MYC is deregulated, resulting in massive perturbation of gene expression. Nevertheless, MYC deregulation alone seems not to be sufficient to drive Burkitt lymphomagenesis. By whole-genome, whole-exome and transcriptome sequencing of four prototypical Burkitt lymphomas with immunoglobulin gene (IG)-MYC translocation, we identified seven recurrently mutated genes. One of these genes, ID3, mapped to a region of focal homozygous loss in Burkitt lymphoma. In an extended cohort, 36 of 53 molecularly defined Burkitt lymphomas (68%) carried potentially damaging mutations of ID3. These were strongly enriched at somatic hypermutation motifs. Only 6 of 47 other B-cell lymphomas with the IG-MYC translocation (13%) carried ID3 mutations. These findings suggest that cooperation between ID3 inactivation and IG-MYC translocation is a hallmark of Burkitt lymphomagenesis.


Clinical Cancer Research | 2010

Differentiation therapy exerts antitumor effects on stem-like glioma cells.

Benito Campos; Feng Wan; Mohammad Farhadi; Aurélie Ernst; Felix Zeppernick; Katrin E. Tagscherer; Rezvan Ahmadi; Jennifer Lohr; Christine Dictus; Georg Gdynia; Stephanie E. Combs; Violaine Goidts; Burkhard Helmke; Volker Eckstein; Wilfried Roth; Peter Lichter; Andreas Unterberg; Bernhard Radlwimmer; Christel Herold-Mende

Purpose: Stem-like tumor cells comprise a highly tumorigenic and therapy-resistant tumor subpopulation, which is believed to substantially influence tumor initiation and therapy resistance in glioma. Currently, therapeutic, drug-induced differentiation is considered as a promising approach to eradicate this tumor-driving cell population; retinoic acid is well known as a potent modulator of differentiation and proliferation in normal stem cells. In glioma, knowledge about the efficacy of retinoic acid–induced differentiation to target the stem-like tumor cell pool could have therapeutic implications. Experimental Design: Stem-like glioma cells (SLGC) were differentiated with all-trans retinoic acid–containing medium to study the effect of differentiation on angiogenesis, invasive growth, as well as radioresistance and chemoresistance of SLGCs. In vivo effects were studied using live microscopy in a cranial window model. Results: Our data suggest that in vitro differentiation of SLGCs induces therapy-sensitizing effects, impairs the secretion of angiogenic cytokines, and disrupts SLGCs motility. Further, ex vivo differentiation reduces tumorigenicity of SLGCs. Finally, we show that all-trans retinoic acid treatment alone can induce antitumor effects in vivo. Conclusions: Altogether, these results highlight the potential of differentiation treatment to target the stem-like cell population in glioblastoma. Clin Cancer Res; 16(10); 2715–28. ©2010 AACR.


Nature | 2014

Decoding the regulatory landscape of medulloblastoma using DNA methylation sequencing

Volker Hovestadt; David T. W. Jones; Simone Picelli; Wei Wang; Marcel Kool; Paul A. Northcott; Marc Sultan; Katharina Stachurski; Marina Ryzhova; Hans Jörg Warnatz; Meryem Ralser; Sonja Brun; Jens Bunt; Natalie Jäger; Kortine Kleinheinz; Serap Erkek; Ursula Weber; Cynthia C. Bartholomae; Christof von Kalle; Chris Lawerenz; Jürgen Eils; Jan Koster; Rogier Versteeg; Till Milde; Olaf Witt; Sabine Schmidt; Stephan Wolf; Torsten Pietsch; Stefan Rutkowski; Wolfram Scheurlen

Epigenetic alterations, that is, disruption of DNA methylation and chromatin architecture, are now acknowledged as a universal feature of tumorigenesis. Medulloblastoma, a clinically challenging, malignant childhood brain tumour, is no exception. Despite much progress from recent genomics studies, with recurrent changes identified in each of the four distinct tumour subgroups (WNT-pathway-activated, SHH-pathway-activated, and the less-well-characterized Group 3 and Group 4), many cases still lack an obvious genetic driver. Here we present whole-genome bisulphite-sequencing data from thirty-four human and five murine tumours plus eight human and three murine normal controls, augmented with matched whole-genome, RNA and chromatin immunoprecipitation sequencing data. This comprehensive data set allowed us to decipher several features underlying the interplay between the genome, epigenome and transcriptome, and its effects on medulloblastoma pathophysiology. Most notable were highly prevalent regions of hypomethylation correlating with increased gene expression, extending tens of kilobases downstream of transcription start sites. Focal regions of low methylation linked to transcription-factor-binding sites shed light on differential transcriptional networks between subgroups, whereas increased methylation due to re-normalization of repressed chromatin in DNA methylation valleys was positively correlated with gene expression. Large, partially methylated domains affecting up to one-third of the genome showed increased mutation rates and gene silencing in a subgroup-specific fashion. Epigenetic alterations also affected novel medulloblastoma candidate genes (for example, LIN28B), resulting in alternative promoter usage and/or differential messenger RNA/microRNA expression. Analysis of mouse medulloblastoma and precursor-cell methylation demonstrated a somatic origin for many alterations. Our data provide insights into the epigenetic regulation of transcription and genome organization in medulloblastoma pathogenesis, which are probably also of importance in a wider developmental and disease context.


Clinical Cancer Research | 2006

Identification of Gains on 1q and Epidermal Growth Factor Receptor Overexpression as Independent Prognostic Markers in Intracranial Ependymoma

Frank Mendrzyk; Andrey Korshunov; Axel Benner; Grischa Toedt; Stefan M. Pfister; Bernhard Radlwimmer; Peter Lichter

Purpose: Pathogenesis of ependymomas is still poorly understood and molecular markers for risk-adapted patient stratification are not available. Our aim was to screen for novel genomic imbalances and prognostic markers in ependymal tumors. Experimental Design: We analyzed 68 sporadic tumors by matrix-based comparative genomic hybridization using DNA microarrays containing >6,400 genomic DNA fragments. Novel recurrent genomic gains were validated by fluorescence in situ hybridization using a tissue microarray consisting of 170 intracranial ependymomas. Candidate genes were also tested for mRNA expression by quantitative real-time PCR, and protein expression was determined by immunohistochemistry on the tissue microarray. Results: Chromosomal gain of 1q correlated with pediatric patients (P = 0.004), intracranial ependymomas (P = 0.05), and tumors of grade III (P = 0.002). Gain of 1q21.1-32.1 was associated with tumor recurrence in intracranial ependymomas (P < 0.001). Furthermore, gain of 1q25 as determined by fluorescence in situ hybridization represented an independent prognostic marker for either recurrence-free survival (P < 0.001) or overall survival (P = 0.003). Recurrent gains at 5p15.33 covering hTERT were validated by immunohistochemistry, and elevated protein levels correlated with adverse prognosis (P = 0.01). In addition to frequent gains and high-level amplification of epidermal growth factor receptor (EGFR) at 7p11.2, immunohistochemistry revealed protein overexpression to be correlated with poor prognosis (P = 0.002). EGFR protein status subdivides intracranial grade II ependymomas into two different risk groups (P = 0.03) as shown by multivariate analysis. Conclusions: Thus, the states of 1q25 and EGFR represent independent prognostic markers for intracranial ependymomas to identify patient subgroups with different risk profiles in further clinical investigations. Moreover, EGFR might serve as therapeutic target for more specific chemotherapy applications.

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Peter Lichter

German Cancer Research Center

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Grischa Toedt

German Cancer Research Center

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Sebastian Barbus

German Cancer Research Center

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Axel Benner

German Cancer Research Center

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Stefan M. Pfister

German Cancer Research Center

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Andreas von Deimling

German Cancer Research Center

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Andrey Korshunov

German Cancer Research Center

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