Reinhard Buettner

Centrum für Integrierte Onkologie, Köln, North Rhine-Westphalia, Germany

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Publications (576)2486.16 Total impact

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    ABSTRACT: Personalised medicine and targeted therapy have revolutionised cancer treatment. However, most patients develop drug resistance and relapse after showing an initial treatment response. Two theories have been postulated; either secondary resistance mutations develop de novo during therapy by mutagenesis or they are present in minor subclones prior to therapy. In this study, these two theories were evaluated in gastrointestinal stromal tumours (GISTs) where most patients develop secondary resistance mutations in the KIT gene during therapy with tyrosine kinase inhibitors. We used a cohort of 33 formalin-fixed, paraffin embedded (FFPE) primary GISTs and their corresponding recurrent tumours with known mutational status. The primary tumours were analysed for the secondary mutations of the recurrences, which had been identified previously. The primary tumours were resected prior to tyrosine kinase inhibitor therapy. Three ultrasensitive, massively parallel sequencing approaches on the GS Junior (Roche, Mannheim, Germany) and the MiSeqTM (Illumina, San Diego, CA, USA) were applied. Additionally, nine fresh-frozen samples resected prior to therapy were analysed for the most common secondary resistance mutations. With a sensitivity level of down to 0.02%, no pre-existing resistant subclones with secondary KIT mutations were detected in primary GISTs. The sensitivity level varied for individual secondary mutations and was limited by sequencing artefacts on both systems. Artificial T > C substitutions at the position of the exon 13 p.V654A mutation, in particular, led to a lower sensitivity, independent from the source of the material. Fresh-frozen samples showed the same range of artificially mutated allele frequencies as the FFPE material. Although we achieved a sufficiently high level of sensitivity, neither in the primary FFPE nor in the fresh-frozen GISTs we were able to detect pre-existing resistant subclones of the corresponding known secondary resistance mutations of the recurrent tumours. This supports the theory that secondary KIT resistance mutations develop under treatment by “de novo” mutagenesis. Alternatively, the detection limit of two mutated clones in 10,000 wild-type clones might not have been high enough or heterogeneous tissue samples, per se, might not be suitable for the detection of very small subpopulations of mutated cells.
    BMC Cancer 12/2015; 15(1). DOI:10.1186/s12885-015-1311-0 · 3.36 Impact Factor
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    OncoImmunology 11/2015; DOI:10.1080/2162402X.2015.1100789 · 6.27 Impact Factor
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    ABSTRACT: Small cell lung carcinoma (SCLC) is the most aggressive entity of lung cancer. Rapid cancer progression and early formation of systemic metastases drive the deadly outcome of SCLC. Recent advances in identifying oncogenes by cancer whole genome sequencing improved the understanding of SCLC carcinogenesis. However, tumor material is often limited in the clinic. Thus, it is a compulsive issue to improve SCLC diagnostics by combining established immunohistochemistry and next generation sequencing. We implemented amplicon-based next generation deep sequencing in our routine diagnostics pipeline to analyze RB1, TP53, EP300 and CREBBP, frequently mutated in SCLC. Thereby, our pipeline combined routine SCLC histology and identification of somatic mutations. We comprehensively analyzed fifty randomly collected SCLC metastases isolated from trachea and lymph nodes in comparison to specimens derived from primary SCLC. SCLC lymph node metastases showed enhanced proliferation and frequently a collapsed keratin cytoskeleton compared to SCLC metastases isolated from trachea. We identified characteristic synchronous mutations in RB1 and TP53 and non-synchronous CREBBP and EP300 mutations. Our data showed the benefit of implementing deep sequencing into routine diagnostics. We here identify oncogenic drivers and simultaneously gain further insights into SCLC tumor biology.
    Experimental and Molecular Pathology 11/2015; 99(3). DOI:10.1016/j.yexmp.2015.11.002 · 2.71 Impact Factor
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    ABSTRACT: Tumor initiation in the intestine can rapidly occur from Lgr5(+) crypt columnar stem cells. Dclk1 is a marker of differentiated Tuft cells and, when coexpressed with Lgr5, also marks intestinal cancer stem cells. Here, we show that Elp3, the catalytic subunit of the Elongator complex, is required for Wnt-driven intestinal tumor initiation and radiation-induced regeneration by maintaining a subpool of Lgr5(+)/Dclk1(+)/Sox9(+) cells. Elp3 deficiency dramatically delayed tumor appearance in Apc-mutated intestinal epithelia and greatly prolonged mice survival without affecting the normal epithelium. Specific ablation of Elp3 in Lgr5(+) cells resulted in marked reduction of polyp formation upon Apc inactivation, in part due to a decreased number of Lgr5(+)/Dclk1(+)/Sox9(+) cells. Mechanistically, Elp3 is induced by Wnt signaling and promotes Sox9 translation, which is needed to maintain the subpool of Lgr5(+)/Dclk1(+) cancer stem cells. Consequently, Elp3 or Sox9 depletion led to similar defects in Dclk1(+) cancer stem cells in ex vivo organoids. Finally, Elp3 deficiency strongly impaired radiation-induced intestinal regeneration, in part because of decreased Sox9 protein levels. Together, our data demonstrate the crucial role of Elp3 in maintaining a subpopulation of Lgr5-derived and Sox9-expressing cells needed to trigger Wnt-driven tumor initiation in the intestine.
    Journal of Experimental Medicine 11/2015; 211(3). DOI:10.1084/jem.20142288 · 12.52 Impact Factor
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    ABSTRACT: Neuroblastoma is a malignant paediatric tumour of the sympathetic nervous system. Roughly half of these tumours regress spontaneously or are cured by limited therapy. By contrast, high-risk neuroblastomas have an unfavourable clinical course despite intensive multimodal treatment, and their molecular basis has remained largely elusive. Here we have performed whole-genome sequencing of 56 neuroblastomas (high-risk, n = 39; low-risk, n = 17) and discovered recurrent genomic rearrangements affecting a chromosomal region at 5p15.33 proximal of the telomerase reverse transcriptase gene (TERT). These rearrangements occurred only in high-risk neuroblastomas (12/39, 31%) in a mutually exclusive fashion with MYCN amplifications and ATRX mutations, which are known genetic events in this tumour type. In an extended case series (n = 217), TERT rearrangements defined a subgroup of high-risk tumours with particularly poor outcome. Despite a large structural diversity of these rearrangements, they all induced massive transcriptional upregulation of TERT. In the remaining high-risk tumours, TERT expression was also elevated in MYCN-amplified tumours, whereas alternative lengthening of telomeres was present in neuroblastomas without TERT or MYCN alterations, suggesting that telomere lengthening represents a central mechanism defining this subtype. The 5p15.33 rearrangements juxtapose the TERT coding sequence to strong enhancer elements, resulting in massive chromatin remodelling and DNA methylation of the affected region. Supporting a functional role of TERT, neuroblastoma cell lines bearing rearrangements or amplified MYCN exhibited both upregulated TERT expression and enzymatic telomerase activity. In summary, our findings show that remodelling of the genomic context abrogates transcriptional silencing of TERT in high-risk neuroblastoma and places telomerase activation in the centre of transformation in a large fraction of these tumours.
    Nature 10/2015; 526(7575). DOI:10.1038/nature14980 · 41.46 Impact Factor
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    ABSTRACT: Small cell lung cancers (SCLCs) and extrapulmonary small cell cancers (SCCs) are very aggressive tumors arising de novo as primary small cell cancer with characteristic genetic lesions in RB1 and TP53. Based on murine models, neuroendocrine stem cells of the terminal bronchioli have been postulated as the cellular origin of primary SCLC. However, both in lung and many other organs, combined small cell/non-small cell tumors and secondary transitions from non-small cell carcinomas upon cancer therapy to neuroendocrine and small cell tumors occur. We define features of 'small cell-ness' based on neuroendocrine markers, characteristic RB1 and TP53 mutations and small cell morphology. Furthermore, here we identify a pathway driving the pathogenesis of secondary SCLC involving inactivating NOTCH mutations, activation of the NOTCH target ASCL1 and canonical WNT-signaling in the context of mutual bi-allelic RB1 and TP53 lesions. Additionaly, we explored ASCL1 dependent RB inactivation by phosphorylation, which is reversible by CDK5 inhibition. We experimentally verify the NOTCH-ASCL1-RB-p53 signaling axis in vitro and validate its activation by genetic alterations in vivo. We analyze clinical tumor samples including SCLC, SCC and pulmonary large cell neuroendocrine carcinomas and adenocarcinomas using amplicon-based Next Generation Sequencing, immunohistochemistry and fluorescence in situ hybridization. In conclusion, we identified a novel pathway underlying rare secondary SCLC which may drive small cell carcinomas in organs other than lung, as well. This article is protected by copyright. All rights reserved. © 2014 Wiley Periodicals, Inc. © 2015 UICC.
    International Journal of Cancer 09/2015; DOI:10.1002/ijc.29835 · 5.09 Impact Factor

  • Cancer Research 08/2015; 75(15 Supplement):LB-210-LB-210. DOI:10.1158/1538-7445.AM2015-LB-210 · 9.33 Impact Factor
  • D Goltz · S Huss · E Ramadori · R Büttner · L Diehl · R Meyer ·
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    ABSTRACT: The pathogenesis of myocardial ischemia-reperfusion injury (MI/R) involves an inflammatory response in the myocardium undergoing reperfusion. Modulation of this response by splenectomy constitutes an option to protect the heart from MI/R. To mimic the effect of splenectomy in a pharmacological approach, the sphingosine-1-phosphate agonist FTY720 was applied at the onset of reperfusion. In a closed chest model of MI/R, infarct size was assessed by triphenyltetrazolium chloride staining after 1 h of ischemia and 24 h of reperfusion, and by Masson trichrome staining 21 d after reperfusion in splenectomised mice, mice post-conditioned with FTY720 i.p. (1 mg kg(-1) ) and controls. In addition, hemodynamic parameters were recorded after 24 h and 21 d by catheterization. Infarct size, and immune cell invasion of phagocytic monocytes investigated by FACS after 24 h of reperfusion were significantly reduced by both splenectomy, and FTY720 treatment. Evaluation after 21 d of reperfusion revealed that FTY720 treated animals had an improved hemodynamic outcome compared to placebo treated as well as splenectomised animals. FTY720 treatment reduced cell injury as effectively as splenectomy by lowering the number of phagocytic monocytes invading the myocardium and ameliorated hemodynamic outcome within the first 21 d. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
    Clinical and Experimental Pharmacology and Physiology 07/2015; 42(11). DOI:10.1111/1440-1681.12465 · 2.37 Impact Factor
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    ABSTRACT: We have sequenced the genomes of 110 small cell lung cancers (SCLC), one of the deadliest human cancers. In nearly all the tumours analysed we found bi-allelic inactivation of TP53 and RB1, sometimes by complex genomic rearrangements. Two tumours with wild-type RB1 had evidence of chromothripsis leading to overexpression of cyclin D1 (encoded by the CCND1 gene), revealing an alternative mechanism of Rb1 deregulation. Thus, loss of the tumour suppressors TP53 and RB1 is obligatory in SCLC. We discovered somatic genomic rearrangements of TP73 that create an oncogenic version of this gene, TP73Δex2/3. In rare cases, SCLC tumours exhibited kinase gene mutations, providing a possible therapeutic opportunity for individual patients. Finally, we observed inactivating mutations in NOTCH family genes in 25% of human SCLC. Accordingly, activation of Notch signalling in a pre-clinical SCLC mouse model strikingly reduced the number of tumours and extended the survival of the mutant mice. Furthermore, neuroendocrine gene expression was abrogated by Notch activity in SCLC cells. This first comprehensive study of somatic genome alterations in SCLC uncovers several key biological processes and identifies candidate therapeutic targets in this highly lethal form of cancer.
    Nature 07/2015; 524(7563). DOI:10.1038/nature14664 · 41.46 Impact Factor
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    ABSTRACT: KRAS is one of the most frequently mutated oncogenes in human cancer. Despite substantial efforts, no clinically applicable strategy has yet been developed to effectively treat KRAS-mutant tumors. Here, we perform a cell-line-based screen and identify strong synergistic interactions between cell-cycle checkpoint-abrogating Chk1- and MK2 inhibitors, specifically in KRAS- and BRAF-driven cells. Mechanistically, we show that KRAS-mutant cancer displays intrinsic genotoxic stress, leading to tonic Chk1- and MK2 activity. We demonstrate that simultaneous Chk1- and MK2 inhibition leads to mitotic catastrophe in KRAS-mutant cells. This actionable synergistic interaction is validated using xenograft models, as well as distinct Kras- or Braf-driven autochthonous murine cancer models. Lastly, we show that combined checkpoint inhibition induces apoptotic cell death in KRAS- or BRAF-mutant tumor cells directly isolated from patients. These results strongly recommend simultaneous Chk1- and MK2 inhibition as a therapeutic strategy for the treatment of KRAS- or BRAF-driven cancers. Copyright © 2015 Elsevier Inc. All rights reserved.
    Cell 07/2015; 162(1):146-159. DOI:10.1016/j.cell.2015.05.053 · 32.24 Impact Factor
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    ABSTRACT: The Network Genomic Medicine Lung Cancer was set up to rapidly translate scientific advances into early clinical trials of targeted therapies in lung cancer performing molecular analyses of more than 3500 patients annually. Because sequential analysis of the relevant driver mutations on fixated samples is challenging in terms of workload, tissue availability, and cost, we established multiplex parallel sequencing in routine diagnostics. The aim was to analyze all therapeutically relevant mutations in lung cancer samples in a high-throughput fashion while significantly reducing turnaround time and amount of input DNA compared with conventional dideoxy sequencing of single polymerase chain reaction amplicons. In this study, we demonstrate the feasibility of a 102 amplicon multiplex polymerase chain reaction followed by sequencing on an Illumina sequencer on formalin-fixed paraffin-embedded tissue in routine diagnostics. Analysis of a validation cohort of 180 samples showed this approach to require significantly less input material and to be more reliable, robust, and cost-effective than conventional dideoxy sequencing. Subsequently, 2657 lung cancer patients were analyzed. We observed that comprehensive biomarker testing provided novel information in addition to histological diagnosis and clinical staging. In 2657 consecutively analyzed lung cancer samples, we identified driver mutations at the expected prevalence. Furthermore we found potentially targetable DDR2 mutations at a frequency of 3% in both adenocarcinomas and squamous cell carcinomas. Overall, our data demonstrate the utility of systematic sequencing analysis in a clinical routine setting and highlight the dramatic impact of such an approach on the availability of therapeutic strategies for the targeted treatment of individual cancer patients.
    Journal of thoracic oncology: official publication of the International Association for the Study of Lung Cancer 06/2015; 10(7). DOI:10.1097/JTO.0000000000000570 · 5.28 Impact Factor
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    ABSTRACT: Liposarcomas (LS) are the most common malignant mesenchymal tumors, with an overall long-term mortality rate of 60%. LS comprise three major subtypes, i.e. well differentiated/dedifferentiated liposarcoma (WDLS/DDLS), myxoid/round cell liposarcoma (MLS), and pleomorphic liposarcoma (PLS). Aiming at the preclinical identification of novel therapeutic options, we here investigate the functional significance of SRC in primary human LS and in LS derived cell lines. Immunohistochemical and western blot analyses reveal relevant levels of activated p-(Tyr416)-SRC in LS of the different subtypes with particular activation in MLS and PLS. Dysregulation of the SRC modifiers CSK and PTP1B was excluded as major reason for the activation of the kinase. Consistent siRNA-mediated knockdown of SRC or inhibition by the SRC inhibitor Dasatinib led to decreased proliferation of LS cell lines of the different subtypes, with MLS cells reacting particularly sensitive in MTT assays. Flow cytometric analyses revealed that this effect was due to a significant decrease in mitotic activity and an induction of apoptosis. SRC inhibition by Dasatinib resulted in dephosphorylation of SRC itself, its interacting partners FAK and IGF-IR as well as its downstream target AKT. Consistent with a particular role of SRC in cell motility, Dasatinib reduced the migratory and invasive potential of MLS cells in Boyden chamber and matrigel chamber assays. In summary, we provide evidence that SRC activation plays an important role in LS biology and therefore represents a potential therapeutic target, particularly in MLS and PLS. This article is protected by copyright. All rights reserved. © 2015 UICC.
    International Journal of Cancer 06/2015; 137(11). DOI:10.1002/ijc.29645 · 5.09 Impact Factor
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    ABSTRACT: Background High resolution molecular studies have demonstrated that the clonal acquisition of gene mutations is an important mechanism that may promote rapid disease progression and drug resistance in chronic lymphocytic leukemia (CLL). Therefore, the early and sensitive detection of such mutations is an important prerequisite for future predictive CLL diagnostics in the clinical setting. Material & Methods Here, we describe a novel, target-specific next generation sequencing (NGS) approach, which combines multiplex PCR-based target enrichment and library generation with ultra-deep high-throughput parallel sequencing using a MiSeq platform. We designed a CLL specific target panel, covering hotspots or complete coding regions of 15 genes known to be recurrently mutated and/or related to B-cell receptor signaling. Results High-throughput sequencing was performed using as little as 40 ng of peripheral blood B-cell DNA from 136 CLL patients and a dilution series of two ATM- or TP53-mutated cell lines, the latter of which demonstrated a limit of mutation detection below 5%. Using a stringent functional assessment algorithm, 102 mutations in 8 genes were identified in CLL patients, including hotspot regions of TP53, SF3B1, NOTCH1, ATM, XPO1, MYD88, DDX3X and the B-cell receptor signaling regulator PTPN6. The presence of mutations was significantly associated with an advanced disease status und molecular markers of an inferior prognosis, such as an unmutated IGHV mutation status or positivity for ZAP70 by flow cytometry. Conclusion In summary, targeted sequencing using an amplicon based library technology allows a resource-efficient and sensitive mutation analysis for diagnostic or exploratory purposes and facilitates molecular subtyping of patient sets with adverse prognosis.
    PLoS ONE 06/2015; 10(6). DOI:10.1371/journal.pone.0129544 · 3.23 Impact Factor
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    ABSTRACT: Baclground: Point mutations and small insertions/deletions (indels) in tumor relevant genes have been identified and proposed as new indicators of prognostic subsets in molecular pathology. Next generation sequencing (NGS) technologies provide the simultaneous analysis of genomic mutations in numerous target regions with high sensitivity. In the present study, multiplex PCR combined with NGS was used to establish a robust, low cost, and high sensitivity pipeline to analyse mutations of diagnostic relevant genes in prostate cancer with therapy resistance and metastases. Material & Methods: A total of more than 100 formalin-fixed and paraffin-embedded (FFPE) prostate cancer tissues including primary prostate carcinoma and the corresponding metastases, as well as prostate carcinoma from patients with transurethral resection or salvage therapy, were used for tumore macrodissection and automated DNA extraction. DNA was quantified by GeneRead quantitative PCR (Qiagen, Hilden GER) and cancer related gebe loci were amplified by multiplex PCR using primer sets designed and provided by Qiagen according to recent literature of whole exome sequencing reports. Specific barcode adapters were ligated and adapter library pools of each sample were sequenced using a MiSeq intrument platform (Illumina). Conventional Sanger sequencing served as a referenece technology. Primary data analysis and generation of fastq files was carried out by means of the MiSeq reporter program. Alignment and variant calling was performed using the CLC Cancer Workbench software (CLCbio, Qiagen). Results: We obtained a total of around 10 million reads per run. Each of the 1,837 amplicons was covered by 400 to 2,000 reads. After seperation of known single nucleotide polymorphisms (SNPs), silent mutations, and aberrations with allelic fraction <5%, mutation hotpsots in many of the 31 tumor specific genes were identified. Frequent mutations were found in TP53, the androgen receptor gene, in the epigenetic writer MLL2, as well as in the MED12 and PIK3CA genes. Conclusions: We established an easy to use, low cost, and fast pipeline of mutation analysis of a prostate cancer specific, hotspot gene panel covering the diagnostic relevant loci by a deep and highly reproducible coverage.
    99. Jahrestagung der deutschen Gesellschaft für Pathologie, Frankfurt/Main; 05/2015
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    ABSTRACT: Salivary gland cancer represents a heterogeneous group of malignant tumors. Due to their low incidence and the existence of multiple morphologically defined subtypes, these tumors are still poorly understood with regard to their molecular pathogenesis and therapeutically relevant genetic alterations. Performing a systematic and comprehensive study covering 13 subtypes of salivary gland cancer, next generation sequencing was done on 84 tissue samples of parotid gland cancer using multiplex PCR for enrichment of cancer related gene loci covering hotspots of 46 cancer genes. Mutations were identified in 22 different genes. The most frequent alterations affected TP53, followed by RAS genes, PIK3CA, SMAD4 and members of the ERB family. HRAS mutations accounted for more than 90% of RAS mutations, occurring especially in epithelial-myoepithelial carcinomas and salivary duct carcinomas. Additional mutations in PIK3CA also affected particularly epithelial-myoepithelial carcinomas and salivary duct carcinomas, occurring simultaneously with HRAS mutations in almost all cases, pointing to an unknown and therapeutically relevant molecular constellation. Interestingly, 14% of tumors revealed mutations in surface growth factor receptor genes including ALK, HER2, ERBB4, FGFR, cMET and RET, which might prove to be targetable by new therapeutic agents. 6% of tumors revealed mutations in SMAD4. In summary, our data provide novel insight into the fundamental molecular heterogeneity of salivary gland cancer, relevant in terms of tumor classification and the establishment of targeted therapeutic concepts.
    Oncotarget 05/2015; 6(20). DOI:10.18632/oncotarget.4015 · 6.36 Impact Factor
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    ABSTRACT: Background: Rearrangements of the ROS1 oncogene occur in about 1-2% of non-small cell lung cancer (NSCLC) patients. While data suggest that the EML4-ALK/MET/ROS1 inhibitor crizotinib is highly effective in these patients, few data is available about the prognostic impact, the predictive value for different treatments, and the genetic heterogeneity of ROS1-positive patients. Methods: 1137 patients with adenocarcinoma of the lung were analyzed regarding their ROS1 status. In positive cases, next-generation sequencing (NGS) was performed. Clinical characteristics, treatments and outcome were assessed. Overall survival (OS) was compared with genetically defined subgroups of ROS1-negative patients. Results: ROS1 status was analyzed in 1035 (91.0%) patients, whereof 19 (1.8%) had ROS1-rearrangement. The median OS of the patients has not been reached yet. Stage IV patients with ROS1-rearrangement had the best OS of all analyzed subgroups (36.7 months, p < 0.001). 9 of 14 (64.2%) patients had at least one response under chemotherapy. Pemetrexed-containing regimens showed higher response rates than paclitaxel-containing ones (80% vs 17%). Estimated mean OS for patients receiving chemotherapy and crizotinib was 5.3 years (median not reached). Ten patients with ROS1-rearrangement (52.6%) harbored additional genetic aberrations in BRAF, MET, EGFR, MAP2K1, and TP53. Conclusions: ROS1-rearangement is not only a strong predictive marker for response to crizotinib, but also seems to be the best prognostic molecular marker in NSCLC reported so far. In stage IV ROS1-positive patients, response to chemotherapy was remarkable high and overall survival regardless of systemic therapy significantly better compared to other genetically defined subgroups including EGFR-mutated and ALK-fusion-positive NSCLC.
    Journal of Clinical Oncology; 05/2015
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    ABSTRACT: Myxoid liposarcomas account for more than one third of liposarcomas and about 10% of all adult soft tissue sarcomas. The tumors are characterized by specific chromosomal translocations leading to the chimeric oncogenes FUS-DDIT3 or EWS1R-DDIT3. The encoded fusion proteins act as aberrant transcription factors. Therefore, we implemented comparative expression analyses using whole-genome microarrays in tumor and fat tissue samples. We aimed at identifying differentially expressed genes which may serve as diagnostic or prognostic biomarkers or as therapeutic targets. Microarray analyses revealed overexpression of FGFR2 and other members of the FGF/FGFR family. Overexpression of FGFR2 was validated by qPCR, immunohistochemistry and western blot analysis in primary tumor samples. Treatment of the myxoid liposarcoma cell lines MLS 402 and MLS 1765 with the FGFR inhibitors PD173074, TKI258 (dovitinib) and BGJ398 as well as specific siRNAs reduced cell proliferation, induced apoptosis and delayed cell migration. Combination of FGFR inhibitors with trabectedin further increased the effect. Our study demonstrates overexpression of FGFR2 and a functional role of FGFR signaling in myxoid liposarcoma. As FGFR inhibition showed effects on proliferation and cell migration and induced apoptosis in vitro, our data indicate the potential use of FGFR inhibitors as a targeted therapy for these tumors.
    Oncotarget 05/2015; 6(24). DOI:10.18632/oncotarget.4046 · 6.36 Impact Factor
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    ABSTRACT: Vimentin is currently used to differentiate between malignant renal carcinomas and benign oncocytomas. Recent reports showing Vimentin positive oncocytomas seriously question the validity of this present diagnostic approach. Vimentin 3 is a spliced variant and ends with a unique C-terminal ending after exon 7 which differentiates it from the full length version that has 9 exons. Therefore, the protein size is different; the full length Vimentin version has a protein size of ~57 kDa and the truncated version of ~47 kDa. We designed an antibody, called Vim3, against the unique C-terminal ending of the Vimentin 3 variant. Using immune histology, immune fluorescence, Western blot, and qRT-PCR analysis, a Vim3 overexpression was detectable exclusively in oncocytoma, making the detection of Vim3 a potential specific marker for benign kidney tumors. This antibody is the first to clearly differentiate benign oncocytoma and the mimicking eosinophilic variants of the RCCs. This differentiation between malignant and benign RCCs is essential for operative planning, follow-up therapy, and patients’ survival. In the future the usage of Vimentin antibodies in routine pathology has to be applied with care. Consideration must be given to Vimentin specific binding epitopes otherwise a misdiagnosis of the patients’ tumor samples may result.
    Disease markers 05/2015; 2015:1-8. DOI:10.1155/2015/368534 · 1.56 Impact Factor

Publication Stats

15k Citations
2,486.16 Total Impact Points


  • 2013-2015
    • Centrum für Integrierte Onkologie
      Köln, North Rhine-Westphalia, Germany
    • Universität Heidelberg
      • Institute of Papyrology
      Heidelburg, Baden-Württemberg, Germany
  • 2011-2015
    • Institute for Pathology, Cologne
      Köln, North Rhine-Westphalia, Germany
  • 2010-2015
    • University of Cologne
      • • Institute of Pathology
      • • Institute of Medical Statistics, Epidemiology and Computer Science
      • • Faculty of Medicine
      Köln, North Rhine-Westphalia, Germany
    • Medical University of Varna
      Odessos, Varna, Bulgaria
  • 2003-2012
    • University of Bonn
      • Institute of Pathology
      Bonn, North Rhine-Westphalia, Germany
  • 2003-2011
    • University of Bonn - Medical Center
      • Institute for Clinical Chemistry and Clinical Pharmacology
      Bonn, North Rhine-Westphalia, Germany
  • 2002-2010
    • Sigmund-Freud-Institut
      Frankfurt, Hesse, Germany
  • 2008
    • Universität des Saarlandes
      Saarbrücken, Saarland, Germany
    • Targos Molecular Pathology GmbH
      Cassel, Hesse, Germany
    • Erasmus MC
      • Department of Pathology
      Rotterdam, South Holland, Netherlands
    • Institut für Pathologie und Molekularpathologie
      Gelsenkirchen, North Rhine-Westphalia, Germany
  • 2007
    • Friedrich-Alexander Universität Erlangen-Nürnberg
      Erlangen, Bavaria, Germany
  • 2006
    • Heidelberg University
      Tiffin, Ohio, United States
    • University of Pretoria
      Πρετόρια/Πόλη του Ακρωτηρίου, Gauteng, South Africa
  • 2005
    • Georg-August-Universität Göttingen
      Göttingen, Lower Saxony, Germany
  • 2000-2005
    • University Hospital RWTH Aachen
      • Division of Internal Medicine
      Aachen, North Rhine-Westphalia, Germany
    • Geisel School of Medicine at Dartmouth
      • Norris Cotton Cancer Center
      Hanover, New Hampshire, United States
  • 2004
    • Klinikum Kassel
      Cassel, Hesse, Germany
    • Università degli Studi di Palermo
      Palermo, Sicily, Italy
  • 2000-2002
    • RWTH Aachen University
      • • Institute of Human Genetics
      • • Institute of Pathology
      Aachen, North Rhine-Westphalia, Germany
  • 2001
    • Lund University
      Lund, Skåne, Sweden
  • 1993-2000
    • University Hospital Regensburg
      • • Institut für Pathologie
      • • Klinik für Dermatologie
      Ratisbon, Bavaria, Germany
  • 1991-2000
    • Universität Regensburg
      • • Department of Dermatology and Venereology
      • • Department of Pathology
      • • Institut für Psychologie
      Ratisbon, Bavaria, Germany
  • 1991-1993
    • University of Texas MD Anderson Cancer Center
      Houston, Texas, United States