Volker Hovestadt
German Cancer Research Center
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Publication
Featured researches published by Volker Hovestadt.
Nature | 2012
Jeremy Schwartzentruber; Andrey Korshunov; Xiao Yang Liu; David T. W. Jones; Elke Pfaff; Karine Jacob; Dominik Sturm; Adam M. Fontebasso; Dong Anh Khuong Quang; Martje Tönjes; Volker Hovestadt; Steffen Albrecht; Marcel Kool; André Nantel; Carolin Konermann; Anders M. Lindroth; Natalie Jäger; Tobias Rausch; Marina Ryzhova; Jan O. Korbel; Thomas Hielscher; Péter Hauser; Miklós Garami; Almos Klekner; László Bognár; Martin Ebinger; Martin U. Schuhmann; Wolfram Scheurlen; Arnulf Pekrun; Michael C. Frühwald
Glioblastoma multiforme (GBM) is a lethal brain tumour in adults and children. However, DNA copy number and gene expression signatures indicate differences between adult and paediatric cases. To explore the genetic events underlying this distinction, we sequenced the exomes of 48 paediatric GBM samples. Somatic mutations in the H3.3-ATRX-DAXX chromatin remodelling pathway were identified in 44% of tumours (21/48). Recurrent mutations in H3F3A, which encodes the replication-independent histone 3 variant H3.3, were observed in 31% of tumours, and led to amino acid substitutions at two critical positions within the histone tail (K27M, G34R/G34V) involved in key regulatory post-translational modifications. Mutations in ATRX (α-thalassaemia/mental retardation syndrome X-linked) and DAXX (death-domain associated protein), encoding two subunits of a chromatin remodelling complex required for H3.3 incorporation at pericentric heterochromatin and telomeres, were identified in 31% of samples overall, and in 100% of tumours harbouring a G34R or G34V H3.3 mutation. Somatic TP53 mutations were identified in 54% of all cases, and in 86% of samples with H3F3A and/or ATRX mutations. Screening of a large cohort of gliomas of various grades and histologies (n = 784) showed H3F3A mutations to be specific to GBM and highly prevalent in children and young adults. Furthermore, the presence of H3F3A/ATRX-DAXX/TP53 mutations was strongly associated with alternative lengthening of telomeres and specific gene expression profiles. This is, to our knowledge, the first report to highlight recurrent mutations in a regulatory histone in humans, and our data suggest that defects of the chromatin architecture underlie paediatric and young adult GBM pathogenesis.
Cancer Cell | 2012
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 | 2012
David T. W. Jones; Natalie Jäger; Marcel Kool; Thomas Zichner; Barbara Hutter; Marc Sultan; Yoon-Jae Cho; Trevor J. Pugh; Volker Hovestadt; Adrian M. Stütz; Tobias Rausch; Hans-Jörg Warnatz; Marina Ryzhova; Sebastian Bender; Dominik Sturm; Sabrina Pleier; Huriye Cin; Elke Pfaff; Laura Sieber; Andrea Wittmann; Marc Remke; Hendrik Witt; Sonja Hutter; Theophilos Tzaridis; Joachim Weischenfeldt; Benjamin Raeder; Meryem Avci; Vyacheslav Amstislavskiy; Marc Zapatka; Ursula Weber
Medulloblastoma is an aggressively growing tumour, arising in the cerebellum or medulla/brain stem. It is the most common malignant brain tumour in children, and shows tremendous biological and clinical heterogeneity. Despite recent treatment advances, approximately 40% of children experience tumour recurrence, and 30% will die from their disease. Those who survive often have a significantly reduced quality of life. Four tumour subgroups with distinct clinical, biological and genetic profiles are currently identified. WNT tumours, showing activated wingless pathway signalling, carry a favourable prognosis under current treatment regimens. SHH tumours show hedgehog pathway activation, and have an intermediate prognosis. Group 3 and 4 tumours are molecularly less well characterized, and also present the greatest clinical challenges. The full repertoire of genetic events driving this distinction, however, remains unclear. Here we describe an integrative deep-sequencing analysis of 125 tumour–normal pairs, conducted as part of the International Cancer Genome Consortium (ICGC) PedBrain Tumor Project. Tetraploidy was identified as a frequent early event in Group 3 and 4 tumours, and a positive correlation between patient age and mutation rate was observed. Several recurrent mutations were identified, both in known medulloblastoma-related genes (CTNNB1, PTCH1, MLL2, SMARCA4) and in genes not previously linked to this tumour (DDX3X, CTDNEP1, KDM6A, TBR1), often in subgroup-specific patterns. RNA sequencing confirmed these alterations, and revealed the expression of what are, to our knowledge, the first medulloblastoma fusion genes identified. Chromatin modifiers were frequently altered across all subgroups. These findings enhance our understanding of the genomic complexity and heterogeneity underlying medulloblastoma, and provide several potential targets for new therapeutics, especially for Group 3 and 4 patients.
Nature Genetics | 2013
David T. W. Jones; Barbara Hutter; Natalie Jäger; Andrey Korshunov; Marcel Kool; Hans-Jörg Warnatz; Thomas Zichner; Sally R. Lambert; Marina Ryzhova; Dong Anh Khuong Quang; Adam M. Fontebasso; Adrian M. Stütz; Sonja Hutter; Marc Zuckermann; Dominik Sturm; Jan Gronych; Bärbel Lasitschka; Sabine Schmidt; Huriye Şeker-Cin; Hendrik Witt; Marc Sultan; Meryem Ralser; Paul A. Northcott; Volker Hovestadt; Sebastian Bender; Elke Pfaff; Sebastian Stark; Damien Faury; Jeremy Schwartzentruber; Jacek Majewski
Pilocytic astrocytoma, the most common childhood brain tumor, is typically associated with mitogen-activated protein kinase (MAPK) pathway alterations. Surgically inaccessible midline tumors are therapeutically challenging, showing sustained tendency for progression and often becoming a chronic disease with substantial morbidities. Here we describe whole-genome sequencing of 96 pilocytic astrocytomas, with matched RNA sequencing (n = 73), conducted by the International Cancer Genome Consortium (ICGC) PedBrain Tumor Project. We identified recurrent activating mutations in FGFR1 and PTPN11 and new NTRK2 fusion genes in non-cerebellar tumors. New BRAF-activating changes were also observed. MAPK pathway alterations affected all tumors analyzed, with no other significant mutations identified, indicating that pilocytic astrocytoma is predominantly a single-pathway disease. Notably, we identified the same FGFR1 mutations in a subset of H3F3A-mutated pediatric glioblastoma with additional alterations in the NF1 gene. Our findings thus identify new potential therapeutic targets in distinct subsets of pilocytic astrocytoma and childhood glioblastoma.
Cancer Research | 2011
Thalia A. Farazi; Hugo M. Horlings; Jelle ten Hoeve; Aleksandra Mihailovic; Hans Halfwerk; Pavel Morozov; Miguel Brown; Markus Hafner; Fabien Reyal; Marieke van Kouwenhove; Bas Kreike; Daoud Sie; Volker Hovestadt; Lodewyk F. A. Wessels; Marc J. van de Vijver; Thomas Tuschl
MicroRNAs (miRNA) regulate many genes critical for tumorigenesis. We profiled miRNAs from 11 normal breast tissues, 17 noninvasive, 151 invasive breast carcinomas, and 6 cell lines by in-house-developed barcoded Solexa sequencing. miRNAs were organized in genomic clusters representing promoter-controlled miRNA expression and sequence families representing seed sequence-dependent miRNA target regulation. Unsupervised clustering of samples by miRNA sequence families best reflected the clustering based on mRNA expression available for this sample set. Clustering and comparative analysis of miRNA read frequencies showed that normal breast samples were separated from most noninvasive ductal carcinoma in situ and invasive carcinomas by increased miR-21 (the most abundant miRNA in carcinomas) and multiple decreased miRNA families (including miR-98/let-7), with most miRNA changes apparent already in the noninvasive carcinomas. In addition, patients that went on to develop metastasis showed increased expression of mir-423, and triple-negative breast carcinomas were most distinct from other tumor subtypes due to upregulation of the mir~17-92 cluster. However, absolute miRNA levels between normal breast and carcinomas did not reveal any significant differences. We also discovered two polymorphic nucleotide variations among the more abundant miRNAs miR-181a (T19G) and miR-185 (T16G), but we did not identify nucleotide variations expected for classical tumor suppressor function associated with miRNAs. The differentiation of tumor subtypes and prediction of metastasis based on miRNA levels is statistically possible but is not driven by deregulation of abundant miRNAs, implicating far fewer miRNAs in tumorigenic processes than previously suggested.
Nature | 2014
Stephen C. Mack; Hendrik Witt; Rosario M. Piro; Lei Gu; Scott Zuyderduyn; A. M. Stütz; Xiaosong Wang; Marco Gallo; Livia Garzia; Kory Zayne; Xiaoyang Zhang; Vijay Ramaswamy; Natalie Jäger; David T. W. Jones; Martin Sill; Trevor J. Pugh; M. Ryzhova; Khalida Wani; David Shih; Renee Head; Marc Remke; S. D. Bailey; Thomas Zichner; Claudia C. Faria; Mark Barszczyk; Sebastian Stark; Huriye Seker-Cin; Sonja Hutter; Pascal Johann; Sebastian Bender
Ependymomas are common childhood brain tumours that occur throughout the nervous system, but are most common in the paediatric hindbrain. Current standard therapy comprises surgery and radiation, but not cytotoxic chemotherapy as it does not further increase survival. Whole-genome and whole-exome sequencing of 47 hindbrain ependymomas reveals an extremely low mutation rate, and zero significant recurrent somatic single nucleotide variants. Although devoid of recurrent single nucleotide variants and focal copy number aberrations, poor-prognosis hindbrain ependymomas exhibit a CpG island methylator phenotype. Transcriptional silencing driven by CpG methylation converges exclusively on targets of the Polycomb repressive complex 2 which represses expression of differentiation genes through trimethylation of H3K27. CpG island methylator phenotype-positive hindbrain ependymomas are responsive to clinical drugs that target either DNA or H3K27 methylation both in vitro and in vivo. We conclude that epigenetic modifiers are the first rational therapeutic candidates for this deadly malignancy, which is epigenetically deregulated but genetically bland.
Cancer Cell | 2013
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.
Nature Genetics | 2012
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.
Acta Neuropathologica | 2015
David E. Reuss; Felix Sahm; Daniel Schrimpf; Benedikt Wiestler; David Capper; Christian Koelsche; Leonille Schweizer; Andrey Korshunov; David T. W. Jones; Volker Hovestadt; Michel Mittelbronn; Jens Schittenhelm; Christel Herold-Mende; Andreas Unterberg; Michael Platten; Michael Weller; Wolfgang Wick; Stefan M. Pfister; Andreas von Deimling
Diffuse gliomas are represented in the 2007 WHO classification as astrocytomas, oligoastrocytomas and oligodendrogliomas of grades II and III and glioblastomas WHO grade IV. Molecular data on these tumors have a major impact on prognosis and therapy of the patients. Consequently, the inclusion of molecular parameters in the WHO definition of brain tumors is being planned and has been forwarded as the “ISN-Haarlem” consensus. We, here, analyze markers of special interest including ATRX, IDH and 1p/19q codeletion in a series of 405 adult patients. Among the WHO 2007 classified tumors were 152 astrocytomas, 61 oligodendrogliomas, 63 oligoastrocytomas and 129 glioblastomas. Following the concepts of the “ISN-Haarlem”, we rediagnosed the series to obtain “integrated” diagnoses with 155 tumors being astrocytomas, 100 oligodendrogliomas and 150 glioblastomas. In a subset of 100 diffuse gliomas from the NOA-04 trial with long-term follow-up data available, the “integrated” diagnosis had a significantly greater prognostic power for overall and progression-free survival compared to WHO 2007. Based on the “integrated” diagnoses, loss of ATRX expression was close to being mutually exclusive to 1p/19q codeletion, with only 2 of 167 ATRX-negative tumors exhibiting 1p/19q codeletion. All but 4 of 141 patients with loss of ATRX expression and diffuse glioma carried either IDH1 or IDH2 mutations. Interestingly, the majority of glioblastoma patients with loss of ATRX expression but no IDH mutations exhibited an H3F3A mutation. Further, all patients with 1p/19 codeletion carried a mutation in IDH1 or IDH2. We present an algorithm based on stepwise analysis with initial immunohistochemistry for ATRX and IDH1-R132H followed by 1p/19q analysis followed by IDH sequencing which reduces the number of molecular analyses and which has a far better association with patient outcome than WHO 2007.
Nature | 2014
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.