Publications by authors named "Charles D Imbusch"

19 Publications

  • Page 1 of 1

AXL Inhibition Represents a Novel Therapeutic Approach in Negative Myeloproliferative Neoplasms.

Hemasphere 2021 Sep 11;5(9):e630. Epub 2021 Aug 11.

Department for Oncology, Hematology and Bone Marrow Transplantation with the Section Pneumology, Hubertus Wald Tumorzentrum, University Comprehensive Cancer Center Hamburg, Germany.

negative myeloproliferative neoplasms (MPNs) consist of essential thrombocythemia, polycythemia vera, and myelofibrosis. The majority of patients harbor the -activating mutation V617F. JAK2 inhibitors were shown to reduce symptom burden and splenomegaly in MPN patients. However, treatment options are limited after failure of JAK2 inhibitors. AXL, a member of the TAM family of receptor tyrosine kinases, mediates survival and therapy resistance of different myeloid cancers including acute myeloid leukemia and chronic myeloid leukemia. We studied the relevance of AXL as a target in MPN using primary patient cells and preclinical disease models. We found that AXL is abundantly activated in MPN cells and that its ligand growth arrest-specific gene 6 is upregulated in MPN patients. Pharmacologic and genetic blockade of AXL impaired viability, decreased proliferation and increased apoptosis of MPN cells. Interestingly, ruxolitinib treatment induced increased phosphorylation of AXL indicating that activation of AXL might mediate resistance to ruxolitinib. Consistently, the AXL inhibitor bemcentinib exerted additive effects with ruxolitinib via impaired STAT3, STAT5, and AKT signaling. Both agents had activity when employed alone and exerted an additive effect on survival and splenomegaly in vivo. Moreover, bemcentinib treatment normalized red blood cell count and hemoglobin levels in vivo. Thus, our data indicate that AXL inhibition represents a novel treatment option in MPN warranting clinical investigation.
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http://dx.doi.org/10.1097/HS9.0000000000000630DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8357258PMC
September 2021

Lorlatinib Induces Durable Disease Stabilization in a Pancreatic Cancer Patient with a ROS1 p.L1950F Mutation: Case Report.

Oncol Res Treat 2021 28;44(9):495-502. Epub 2021 Jul 28.

Department of Hematology, Oncology and Bone Marrow Transplantation with Section Pneumology, Hubertus Wald Tumorzentrum, University Comprehensive Cancer Center Hamburg, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

Introduction: The prognosis of pancreatic cancer has improved only modestly in recent years. This is partly due to the lack of development in precision oncology including immune oncology in this entity. Rearrangements of the proto-oncogene tyrosine protein kinase ROS1 gene represent driver alterations found especially in lung cancer. Tyrosine kinase inhibitors (TKI) with activity against ROS1 including lorlatinib substantially improved the outcome of this patient population. Anecdotal evidence reports treatment of pancreatic cancer harboring ROS1 fusions with ROS1 TKI, but data concerning treatment of patients with ROS1 point mutations are lacking.

Case Presentation: This case describes a pancreatic cancer patient harboring a ROS1 point mutation that occurred without an underlying ROS1 rearrangement and thus not in the resistance situation. The heavily pretreated patient showed a strong decrease of the tumor biomarkers (CA19-9 and CEA) and radiologically a durable stable disease to the targeted treatment with lorlatinib, thereby achieving a progression-free survival of 12 months.

Conclusion: Our data are the first to show a clinical benefit from targeted treatment with ROS1 TKI in a cancer patient with a thus far undescribed ROS1 point mutation without a concomitant ROS1 rearrangement. Furthermore, they indicate that ROS1 could be an oncogenic driver in pancreatic cancer. This subgroup could be eligible for targeted treatments, which may contribute to the urgently needed improvement in patient outcome.
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http://dx.doi.org/10.1159/000517616DOI Listing
October 2021

Deconvolution of sarcoma methylomes reveals varying degrees of immune cell infiltrates with association to genomic aberrations.

J Transl Med 2021 05 12;19(1):204. Epub 2021 May 12.

Division of Applied Bioinformatics, German Cancer Research Center (DKFZ), Heidelberg, Germany.

Background: Soft-tissue sarcomas (STS) are a heterogeneous group of mesenchymal tumors for which response to immunotherapies is not well established. Therefore, it is important to risk-stratify and identify STS patients who will most likely benefit from these treatments.

Results: To reveal shared and distinct methylation signatures present in STS, we performed unsupervised deconvolution of DNA methylation data from the TCGA sarcoma and an independent validation cohort. We showed that leiomyosarcoma can be subclassified into three distinct methylation groups. More importantly, we identified a component associated with tumor-infiltrating leukocytes, which suggests varying degrees of immune cell infiltration in STS subtypes and an association with prognosis. We further investigated the genomic alterations that may influence tumor infiltration by leukocytes including RB1 loss in undifferentiated pleomorphic sarcomas and ELK3 amplification in dedifferentiated liposarcomas.

Conclusions: In summary, we have leveraged unsupervised methylation-based deconvolution to characterize the immune compartment and molecularly stratify subtypes in STS, which may benefit precision medicine in the future.
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http://dx.doi.org/10.1186/s12967-021-02858-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8117561PMC
May 2021

Single-cell chromatin accessibility landscape identifies tissue repair program in human regulatory T cells.

Immunity 2021 04 30;54(4):702-720.e17. Epub 2021 Mar 30.

Regensburg Center for Interventional Immunology (RCI); Chair for Immunology, University Regensburg, 93053 Regensburg, Germany. Electronic address:

Murine regulatory T (Treg) cells in tissues promote tissue homeostasis and regeneration. We sought to identify features that characterize human Treg cells with these functions in healthy tissues. Single-cell chromatin accessibility profiles of murine and human tissue Treg cells defined a conserved, microbiota-independent tissue-repair Treg signature with a prevailing footprint of the transcription factor BATF. This signature, combined with gene expression profiling and TCR fate mapping, identified a population of tissue-like Treg cells in human peripheral blood that expressed BATF, chemokine receptor CCR8 and HLA-DR. Human BATFCCR8 Treg cells from normal skin and adipose tissue shared features with nonlymphoid T follicular helper-like (Tfh-like) cells, and induction of a Tfh-like differentiation program in naive human Treg cells partially recapitulated tissue Treg regenerative characteristics, including wound healing potential. Human BATFCCR8 Treg cells from healthy tissue share features with tumor-resident Treg cells, highlighting the importance of understanding the context-specific functions of these cells.
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http://dx.doi.org/10.1016/j.immuni.2021.03.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8050210PMC
April 2021

Aggressive PDACs Show Hypomethylation of Repetitive Elements and the Execution of an Intrinsic IFN Program Linked to a Ductal Cell of Origin.

Cancer Discov 2021 03 15;11(3):638-659. Epub 2020 Oct 15.

German Cancer Consortium (DKTK), Heidelberg, Germany.

Pancreatic ductal adenocarcinoma (PDAC) is characterized by extensive desmoplasia, which challenges the molecular analyses of bulk tumor samples. Here we FACS-purified epithelial cells from human PDAC and normal pancreas and derived their genome-wide transcriptome and DNA methylome landscapes. Clustering based on DNA methylation revealed two distinct PDAC groups displaying different methylation patterns at regions encoding repeat elements. Methylation tumors are characterized by higher expression of endogenous retroviral transcripts and double-stranded RNA sensors, which lead to a cell-intrinsic activation of an interferon signature (IFNsign). This results in a protumorigenic microenvironment and poor patient outcome. Methylation/IFNsign and Methylation/IFNsign PDAC cells preserve lineage traits, respective of normal ductal or acinar pancreatic cells. Moreover, ductal-derived / mouse PDACs show higher expression of IFNsign compared with acinar-derived counterparts. Collectively, our data point to two different origins and etiologies of human PDACs, with the aggressive Methylation/IFNsign subtype potentially targetable by agents blocking intrinsic IFN signaling. SIGNIFICANCE: The mutational landscapes of PDAC alone cannot explain the observed interpatient heterogeneity. We identified two PDAC subtypes characterized by differential DNA methylation, preserving traits from normal ductal/acinar cells associated with IFN signaling. Our work suggests that epigenetic traits and the cell of origin contribute to PDAC heterogeneity..
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http://dx.doi.org/10.1158/2159-8290.CD-20-1202DOI Listing
March 2021

Quantitative Proteomics Identifies TCF1 as a Negative Regulator of Foxp3 Expression in Conventional T Cells.

iScience 2020 May 4;23(5):101127. Epub 2020 May 4.

Chair for Immunology, Regensburg University, Franz-Josef-Strauss-Allee 11, 93053 Regensburg, Germany; Regensburg Center for Interventional Immunology (RCI), Franz-Josef-Strauss-Allee 11, 93053 Regensburg, Germany; Immune Tolerance Group, Tumor Immunology Program, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany. Electronic address:

Regulatory T cells are important regulators of the immune system and have versatile functions for the homeostasis and repair of tissues. They express the forkhead box transcription factor Foxp3 as a lineage-defining protein. Negative regulators of Foxp3 expression are not well understood. Here, we generated double-stranded DNA probes complementary to the Foxp3 promoter sequence and performed a pull-down with nuclear protein in vitro, followed by elution of bound proteins and quantitative mass spectrometry. Of the Foxp3-promoter-binding transcription factors identified with this approach, one was T cell factor 1 (TCF1). Using viral over-expression, we identified TCF1 as a repressor of Foxp3 expression. In TCF1-deficient animals, increased levels of Foxp3CD25 T cells were identified. CRISPR-Cas9 knockout studies in primary human and mouse conventional CD4 T (T) cells revealed that TCF1 protects T cells from inadvertent Foxp3 expression. Our data implicate a role of TCF1 in suppressing Foxp3 expression in activated T cells.
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http://dx.doi.org/10.1016/j.isci.2020.101127DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7229326PMC
May 2020

Precursors for Nonlymphoid-Tissue Treg Cells Reside in Secondary Lymphoid Organs and Are Programmed by the Transcription Factor BATF.

Immunity 2020 02 7;52(2):295-312.e11. Epub 2020 Jan 7.

Regensburg Center for Interventional Immunology (RCI), Franz-Josef-Strauss-Allee 11, 93053 Regensburg, Germany; Chair for Immunology, Regensburg University, Franz-Josef-Strauss-Allee 11, 93053 Regensburg, Germany; Immune Tolerance Group, Tumor Immunology Program, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany. Electronic address:

Specialized regulatory T (Treg) cells accumulate and perform homeostatic and regenerative functions in nonlymphoid tissues. Whether common precursors for nonlymphoid-tissue Treg cells exist and how they differentiate remain elusive. Using transcription factor nuclear factor, interleukin 3 regulated (Nfil3) reporter mice and single-cell RNA-sequencing (scRNA-seq), we identified two precursor stages of interleukin 33 (IL-33) receptor ST2-expressing nonlymphoid tissue Treg cells, which resided in the spleen and lymph nodes. Global chromatin profiling of nonlymphoid tissue Treg cells and the two precursor stages revealed a stepwise acquisition of chromatin accessibility and reprogramming toward the nonlymphoid-tissue Treg cell phenotype. Mechanistically, we identified and validated the transcription factor Batf as the driver of the molecular tissue program in the precursors. Understanding this tissue development program will help to harness regenerative properties of tissue Treg cells for therapy.
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http://dx.doi.org/10.1016/j.immuni.2019.12.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7026712PMC
February 2020

Rbpj expression in regulatory T cells is critical for restraining T2 responses.

Nat Commun 2019 04 8;10(1):1621. Epub 2019 Apr 8.

Chair for Immunology, University Regensburg and University Hospital Regensburg, Franz-Josef-Strauss-Allee 11, 93053, Regensburg, Germany.

The transcriptional regulator Rbpj is involved in T-helper (T) subset polarization, but its function in T cells remains unclear. Here we show that T-specific Rbpj deletion leads to splenomegaly and lymphadenopathy despite increased numbers of T cells with a polyclonal TCR repertoire. A specific defect of Rbpj-deficient T cells in controlling T2 polarization and B cell responses is observed, leading to the spontaneous formation of germinal centers and a T2-associated immunoglobulin class switch. The observed phenotype is environment-dependent and can be induced by infection with parasitic nematodes. Rbpj-deficient T cells adopt open chromatin landscapes and gene expression profiles reminiscent of tissue-derived T2-polarized T cells, with a prevailing signature of the transcription factor Gata-3. Taken together, our study suggests that T cells require Rbpj to specifically restrain T2 responses, including their own excessive T2-like differentiation potential.
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http://dx.doi.org/10.1038/s41467-019-09276-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6453958PMC
April 2019

Generation of Whole Genome Bisulfite Sequencing Libraries from Very Low DNA Input.

Methods Mol Biol 2019 ;1956:229-248

Cancer Epigenomics, German Cancer Research Center (DKFZ), Heidelberg, Germany.

DNA methylation changes are dynamic processes which occur at cytosines of CpG dinucleotides and contribute to normal development but also to diseases. DNA methylation changes are most effective in promoters and enhancers, the former frequently being CpG-rich and the latter, in contrast, CpG-poor. Many genome-wide methods for DNA methylation analysis interrogate predominantly CpG-rich regions and, hence, spare enhancers and other potentially important genomic regions. Whole genome bisulfite sequencing (WGBS), in contrast, analyzes the DNA methylome in its entirety. Standard tagmentation-based whole genome bisulfite sequencing (TWGBS) is a Tn5 transposon-based method which requires only 30 ng of human input DNA and, hence, is particularly suited for precious biological samples like cells sorted by flow cytometry or laser capture microdissected tissue specimens. In the standard version, tagmentation generates DNA fragments flanked by uniform sequencing adapters. In a subsequent step, the non-covalently bound adapter oligonucleotide needs to be replaced by a novel oligonucleotide to provide the proper adapter sequence for the reverse strand in paired-end sequencing. The presented protocol describes an improved, simplified version of TWGBS where the inefficient oligo-replacement is circumvented by usage of a sequencing-compatible transposase-adapter complex. Consequently, genomic DNA of only a few hundred human cells is required to interrogate the complete human DNA methylome.
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http://dx.doi.org/10.1007/978-1-4939-9151-8_10DOI Listing
July 2019

Integrative analysis of single-cell expression data reveals distinct regulatory states in bidirectional promoters.

Epigenetics Chromatin 2018 11 10;11(1):66. Epub 2018 Nov 10.

Excellence Cluster for Multimodal Computing and Interaction, Saarland Informatics Campus, Saarland University, Campus E1 7, Saarbrücken, 66123, Germany.

Background: Bidirectional promoters (BPs) are prevalent in eukaryotic genomes. However, it is poorly understood how the cell integrates different epigenomic information, such as transcription factor (TF) binding and chromatin marks, to drive gene expression at BPs. Single-cell sequencing technologies are revolutionizing the field of genome biology. Therefore, this study focuses on the integration of single-cell RNA-seq data with bulk ChIP-seq and other epigenetics data, for which single-cell technologies are not yet established, in the context of BPs.

Results: We performed integrative analyses of novel human single-cell RNA-seq (scRNA-seq) data with bulk ChIP-seq and other epigenetics data. scRNA-seq data revealed distinct transcription states of BPs that were previously not recognized. We find associations between these transcription states to distinct patterns in structural gene features, DNA accessibility, histone modification, DNA methylation and TF binding profiles.

Conclusions: Our results suggest that a complex interplay of all of these elements is required to achieve BP-specific transcriptional output in this specialized promoter configuration. Further, our study implies that novel statistical methods can be developed to deconvolute masked subpopulations of cells measured with different bulk epigenomic assays using scRNA-seq data.
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http://dx.doi.org/10.1186/s13072-018-0236-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6230222PMC
November 2018

Genome-wide DNA-methylation landscape defines specialization of regulatory T cells in tissues.

Nat Immunol 2017 Oct 7;18(10):1160-1172. Epub 2017 Aug 7.

Immune Tolerance Research Group, German Cancer Research Center (DKFZ), Heidelberg, Germany.

Regulatory T cells (T cells) perform two distinct functions: they maintain self-tolerance, and they support organ homeostasis by differentiating into specialized tissue T cells. We found that epigenetic modifications defined the molecular characteristics of tissue T cells. Tagmentation-based whole-genome bisulfite sequencing revealed more than 11,000 regions that were methylated differentially in pairwise comparisons of tissue T cell populations and lymphoid T cells. Similarities in the epigenetic landscape led to the identification of a common tissue T cell population that was present in many organs and was characterized by gain and loss of DNA methylation that included many gene sites associated with the T2 subset of helper T cells, such as the gene encoding cytokine IL-33 receptor ST2, as well as the production of tissue-regenerative factors. Furthermore, the ST2-expressing population was dependent on the transcriptional regulator BATF and could be expanded by IL-33. Thus, tissue T cells integrate multiple waves of epigenetic reprogramming that define their tissue-restricted specialization.
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http://dx.doi.org/10.1038/ni.3799DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5912503PMC
October 2017

The whole-genome landscape of medulloblastoma subtypes.

Nature 2017 07;547(7663):311-317

Division of Theoretical Bioinformatics, German Cancer Research Center (DKFZ), Heidelberg, Germany.

Current therapies for medulloblastoma, a highly malignant childhood brain tumour, impose debilitating effects on the developing child, and highlight the need for molecularly targeted treatments with reduced toxicity. Previous studies have been unable to identify the full spectrum of driver genes and molecular processes that operate in medulloblastoma subgroups. Here we analyse the somatic landscape across 491 sequenced medulloblastoma samples and the molecular heterogeneity among 1,256 epigenetically analysed cases, and identify subgroup-specific driver alterations that include previously undiscovered actionable targets. Driver mutations were confidently assigned to most patients belonging to Group 3 and Group 4 medulloblastoma subgroups, greatly enhancing previous knowledge. New molecular subtypes were differentially enriched for specific driver events, including hotspot in-frame insertions that target KBTBD4 and 'enhancer hijacking' events that activate PRDM6. Thus, the application of integrative genomics to an extensive cohort of clinical samples derived from a single childhood cancer entity revealed a series of cancer genes and biologically relevant subtype diversity that represent attractive therapeutic targets for the treatment of patients with medulloblastoma.
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http://dx.doi.org/10.1038/nature22973DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5905700PMC
July 2017

DNMT and HDAC inhibitors induce cryptic transcription start sites encoded in long terminal repeats.

Nat Genet 2017 Jul 12;49(7):1052-1060. Epub 2017 Jun 12.

Department of Genetics, The Edison Family Center for Genome Sciences &Systems Biology, Washington University School of Medicine, St. Louis, Missouri, USA.

Several mechanisms of action have been proposed for DNA methyltransferase and histone deacetylase inhibitors (DNMTi and HDACi), primarily based on candidate-gene approaches. However, less is known about their genome-wide transcriptional and epigenomic consequences. By mapping global transcription start site (TSS) and chromatin dynamics, we observed the cryptic transcription of thousands of treatment-induced non-annotated TSSs (TINATs) following DNMTi and HDACi treatment. The resulting transcripts frequently splice into protein-coding exons and encode truncated or chimeric ORFs translated into products with predicted abnormal or immunogenic functions. TINAT transcription after DNMTi treatment coincided with DNA hypomethylation and gain of classical promoter histone marks, while HDACi specifically induced a subset of TINATs in association with H2AK9ac, H3K14ac, and H3K23ac. Despite this mechanistic difference, both inhibitors convergently induced transcription from identical sites, as we found TINATs to be encoded in solitary long terminal repeats of the ERV9/LTR12 family, which are epigenetically repressed in virtually all normal cells.
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http://dx.doi.org/10.1038/ng.3889DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6005702PMC
July 2017

Epigenomic Profiling of Human CD4 T Cells Supports a Linear Differentiation Model and Highlights Molecular Regulators of Memory Development.

Immunity 2016 11;45(5):1148-1161

Applied Bioinformatics, Deutsches Krebsforschungszentrum, 59120 Heidelberg, Germany.

The impact of epigenetics on the differentiation of memory T (Tmem) cells is poorly defined. We generated deep epigenomes comprising genome-wide profiles of DNA methylation, histone modifications, DNA accessibility, and coding and non-coding RNA expression in naive, central-, effector-, and terminally differentiated CD45RA CD4 Tmem cells from blood and CD69 Tmem cells from bone marrow (BM-Tmem). We observed a progressive and proliferation-associated global loss of DNA methylation in heterochromatic parts of the genome during Tmem cell differentiation. Furthermore, distinct gradually changing signatures in the epigenome and the transcriptome supported a linear model of memory development in circulating T cells, while tissue-resident BM-Tmem branched off with a unique epigenetic profile. Integrative analyses identified candidate master regulators of Tmem cell differentiation, including the transcription factor FOXP1. This study highlights the importance of epigenomic changes for Tmem cell biology and demonstrates the value of epigenetic data for the identification of lineage regulators.
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http://dx.doi.org/10.1016/j.immuni.2016.10.022DOI Listing
November 2016

DNA methylation dynamics during B cell maturation underlie a continuum of disease phenotypes in chronic lymphocytic leukemia.

Nat Genet 2016 Mar 18;48(3):253-64. Epub 2016 Jan 18.

Division of Epigenomics and Cancer Risk Factors, German Cancer Research Center (DKFZ), Heidelberg, Germany.

Charting differences between tumors and normal tissue is a mainstay of cancer research. However, clonal tumor expansion from complex normal tissue architectures potentially obscures cancer-specific events, including divergent epigenetic patterns. Using whole-genome bisulfite sequencing of normal B cell subsets, we observed broad epigenetic programming of selective transcription factor binding sites coincident with the degree of B cell maturation. By comparing normal B cells to malignant B cells from 268 patients with chronic lymphocytic leukemia (CLL), we showed that tumors derive largely from a continuum of maturation states reflected in normal developmental stages. Epigenetic maturation in CLL was associated with an indolent gene expression pattern and increasingly favorable clinical outcomes. We further uncovered that most previously reported tumor-specific methylation events are normally present in non-malignant B cells. Instead, we identified a potential pathogenic role for transcription factor dysregulation in CLL, where excess programming by EGR and NFAT with reduced EBF and AP-1 programming imbalances the normal B cell epigenetic program.
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http://dx.doi.org/10.1038/ng.3488DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4963005PMC
March 2016

Enhancer hijacking activates GFI1 family oncogenes in medulloblastoma.

Nature 2014 Jul 22;511(7510):428-34. Epub 2014 Jun 22.

Data Management Facility, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg 69120, Germany.

Medulloblastoma is a highly malignant paediatric brain tumour currently treated with a combination of surgery, radiation and chemotherapy, posing a considerable burden of toxicity to the developing child. Genomics has illuminated the extensive intertumoral heterogeneity of medulloblastoma, identifying four distinct molecular subgroups. Group 3 and group 4 subgroup medulloblastomas account for most paediatric cases; yet, oncogenic drivers for these subtypes remain largely unidentified. Here we describe a series of prevalent, highly disparate genomic structural variants, restricted to groups 3 and 4, resulting in specific and mutually exclusive activation of the growth factor independent 1 family proto-oncogenes, GFI1 and GFI1B. Somatic structural variants juxtapose GFI1 or GFI1B coding sequences proximal to active enhancer elements, including super-enhancers, instigating oncogenic activity. Our results, supported by evidence from mouse models, identify GFI1 and GFI1B as prominent medulloblastoma oncogenes and implicate 'enhancer hijacking' as an efficient mechanism driving oncogene activation in a childhood cancer.
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http://dx.doi.org/10.1038/nature13379DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4201514PMC
July 2014

Recurrent somatic alterations of FGFR1 and NTRK2 in pilocytic astrocytoma.

Nat Genet 2013 Aug 30;45(8):927-32. Epub 2013 Jun 30.

Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ), Heidelberg, Germany.

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.
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http://dx.doi.org/10.1038/ng.2682DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3951336PMC
August 2013
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