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  • 1
    Publication Date: 2018-12-07
    Description: Neuroblastoma is a pediatric tumor of the sympathetic nervous system. Its clinical course ranges from spontaneous tumor regression to fatal progression. To investigate the molecular features of the divergent tumor subtypes, we performed genome sequencing on 416 pretreatment neuroblastomas and assessed telomere maintenance mechanisms in 208 of these tumors. We found that patients whose tumors lacked telomere maintenance mechanisms had an excellent prognosis, whereas the prognosis of patients whose tumors harbored telomere maintenance mechanisms was substantially worse. Survival rates were lowest for neuroblastoma patients whose tumors harbored telomere maintenance mechanisms in combination with RAS and/or p53 pathway mutations. Spontaneous tumor regression occurred both in the presence and absence of these mutations in patients with telomere maintenance–negative tumors. On the basis of these data, we propose a mechanistic classification of neuroblastoma that may benefit the clinical management of patients.
    Keywords: Medicine, Diseases
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Geosciences , Computer Science , Medicine , Natural Sciences in General , Physics
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  • 2
    Keywords: TUMORS ; ASSOCIATION ; WOMEN ; ORAL-CONTRACEPTIVES ; HISTOLOGIC TYPE ; LIFE-STYLE FACTORS ; inflammation ; TOBACCO USE ; HORMONE-THERAPY ; BORDERLINE
    Abstract: PURPOSE: The majority of previous studies have observed an increased risk of mucinous ovarian tumors associated with cigarette smoking, but the association with other histological types is unclear. In a large pooled analysis, we examined the risk of epithelial ovarian cancer associated with multiple measures of cigarette smoking with a focus on characterizing risks according to tumor behavior and histology. METHODS: We used data from 21 case-control studies of ovarian cancer (19,066 controls, 11,972 invasive and 2,752 borderline cases). Study-specific odds ratios (OR) and 95 % confidence intervals (CI) were obtained from logistic regression models and combined into a pooled odds ratio using a random effects model. RESULTS: Current cigarette smoking increased the risk of invasive mucinous (OR = 1.31; 95 % CI: 1.03-1.65) and borderline mucinous ovarian tumors (OR = 1.83; 95 % CI: 1.39-2.41), while former smoking increased the risk of borderline serous ovarian tumors (OR = 1.30; 95 % CI: 1.12-1.50). For these histological types, consistent dose-response associations were observed. No convincing associations between smoking and risk of invasive serous and endometrioid ovarian cancer were observed, while our results provided some evidence of a decreased risk of invasive clear cell ovarian cancer. CONCLUSIONS: Our results revealed marked differences in the risk profiles of histological types of ovarian cancer with regard to cigarette smoking, although the magnitude of the observed associations was modest. Our findings, which may reflect different etiologies of the histological types, add to the fact that ovarian cancer is a heterogeneous disease.
    Type of Publication: Journal article published
    PubMed ID: 23456270
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  • 3
    Publication Date: 2015-10-16
    Description: 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.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Peifer, Martin -- Hertwig, Falk -- Roels, Frederik -- Dreidax, Daniel -- Gartlgruber, Moritz -- Menon, Roopika -- Kramer, Andrea -- Roncaioli, Justin L -- Sand, Frederik -- Heuckmann, Johannes M -- Ikram, Fakhera -- Schmidt, Rene -- Ackermann, Sandra -- Engesser, Anne -- Kahlert, Yvonne -- Vogel, Wenzel -- Altmuller, Janine -- Nurnberg, Peter -- Thierry-Mieg, Jean -- Thierry-Mieg, Danielle -- Mariappan, Aruljothi -- Heynck, Stefanie -- Mariotti, Erika -- Henrich, Kai-Oliver -- Gloeckner, Christian -- Bosco, Graziella -- Leuschner, Ivo -- Schweiger, Michal R -- Savelyeva, Larissa -- Watkins, Simon C -- Shao, Chunxuan -- Bell, Emma -- Hofer, Thomas -- Achter, Viktor -- Lang, Ulrich -- Theissen, Jessica -- Volland, Ruth -- Saadati, Maral -- Eggert, Angelika -- de Wilde, Bram -- Berthold, Frank -- Peng, Zhiyu -- Zhao, Chen -- Shi, Leming -- Ortmann, Monika -- Buttner, Reinhard -- Perner, Sven -- Hero, Barbara -- Schramm, Alexander -- Schulte, Johannes H -- Herrmann, Carl -- O'Sullivan, Roderick J -- Westermann, Frank -- Thomas, Roman K -- Fischer, Matthias -- England -- Nature. 2015 Oct 29;526(7575):700-4. doi: 10.1038/nature14980. Epub 2015 Oct 14.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Translational Genomics, Center of Integrated Oncology Cologne-Bonn, Medical Faculty, University of Cologne, 50931 Cologne, Germany. ; Center for Molecular Medicine Cologne (CMMC), University of Cologne, 50931 Cologne, Germany. ; Department of Pediatric Oncology and Hematology, University Children's Hospital of Cologne, Medical Faculty, University of Cologne, 50937 Cologne, Germany. ; Division Neuroblastoma Genomics (B087), German Cancer Research Center, 69120 Heidelberg, Germany. ; Department of Prostate Cancer Research, Institute of Pathology, Center for Integrated Oncology Cologne-Bonn, University Hospital of Bonn, 53127 Bonn, Germany. ; NEO New Oncology AG, 51105 Cologne, Germany. ; Department of Pharmacology and Chemical Biology, University of Pittsburgh Cancer Institute (UPCI), Hillman Cancer Center, Pittsburgh, Pennsylvania 15213, USA. ; Cologne Center for Genomics, University of Cologne, 50931 Cologne, Germany. ; Institute of Biostatistics and Clinical Research, University of Munster, 48149 Munster, Germany. ; Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, 50931 Cologne, Germany. ; National Center for Biotechnology Information, National Library of Medicine, National Institutes of Health, Bethesda, Maryland 20894, USA. ; Department of Pathology, University of Kiel, 24118 Kiel, Germany. ; Functional Epigenomics, University of Cologne, 50931 Cologne, Germany. ; Department of Cell Biology, Center for Biologic Imaging, University of Pittsburgh, Pittsburgh, Pennsylvania 15261, USA. ; Division of Theoretical Systems Biology, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany. ; Computing Center, University of Cologne, 50931 Cologne, Germany. ; Department of Informatics, University of Cologne, 50931 Cologne, Germany. ; Division of Biostatistics, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany. ; Department of Pediatric Oncology and Hematology, Charite University Medical Center Berlin, 10117 Berlin, Germany. ; Center for Medical Genetics, Ghent University, 9000 Ghent, Belgium. ; BGI-Shenzhen, Bei Shan Industrial Zone, Yantian District, Shenzhen, Guangdong, 518083 China. ; Center for Pharmacogenomics and Fudan-Zhangjiang Center for Clinical Genomics, State Key Laboratory of Genetic Engineering and MOE Key Laboratory of Contemporary Anthropology School of Pharmacy and School of Life Sciences, Fudan University, Shanghai 201203, China. ; Department of Pathology, University of Cologne, 50937 Cologne, Germany. ; Department of Pediatric Oncology and Hematology, University Children's Hospital, 45147 Essen, Germany. ; German Cancer Consortium (DKTK), 10117 Berlin, Germany. ; German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany. ; Institute of Pharmacy and Molecular Biotechnology, University of Heidelberg, 69120 Heidelberg, Germany. ; Bioquant Center, University of Heidelberg, 69120 Heidelberg, Germany. ; Division of Theoretical Bioinformatics, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany. ; Max Planck Institute for Metabolism Research, 50931 Cologne, Germany.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26466568" target="_blank"〉PubMed〈/a〉
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 4
    Publication Date: 2015-07-15
    Description: 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, TP73Deltaex2/3. 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.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉George, Julie -- Lim, Jing Shan -- Jang, Se Jin -- Cun, Yupeng -- Ozretic, Luka -- Kong, Gu -- Leenders, Frauke -- Lu, Xin -- Fernandez-Cuesta, Lynnette -- Bosco, Graziella -- Muller, Christian -- Dahmen, Ilona -- Jahchan, Nadine S -- Park, Kwon-Sik -- Yang, Dian -- Karnezis, Anthony N -- Vaka, Dedeepya -- Torres, Angela -- Wang, Maia Segura -- Korbel, Jan O -- Menon, Roopika -- Chun, Sung-Min -- Kim, Deokhoon -- Wilkerson, Matt -- Hayes, Neil -- Engelmann, David -- Putzer, Brigitte -- Bos, Marc -- Michels, Sebastian -- Vlasic, Ignacija -- Seidel, Danila -- Pinther, Berit -- Schaub, Philipp -- Becker, Christian -- Altmuller, Janine -- Yokota, Jun -- Kohno, Takashi -- Iwakawa, Reika -- Tsuta, Koji -- Noguchi, Masayuki -- Muley, Thomas -- Hoffmann, Hans -- Schnabel, Philipp A -- Petersen, Iver -- Chen, Yuan -- Soltermann, Alex -- Tischler, Verena -- Choi, Chang-min -- Kim, Yong-Hee -- Massion, Pierre P -- Zou, Yong -- Jovanovic, Dragana -- Kontic, Milica -- Wright, Gavin M -- Russell, Prudence A -- Solomon, Benjamin -- Koch, Ina -- Lindner, Michael -- Muscarella, Lucia A -- la Torre, Annamaria -- Field, John K -- Jakopovic, Marko -- Knezevic, Jelena -- Castanos-Velez, Esmeralda -- Roz, Luca -- Pastorino, Ugo -- Brustugun, Odd-Terje -- Lund-Iversen, Marius -- Thunnissen, Erik -- Kohler, Jens -- Schuler, Martin -- Botling, Johan -- Sandelin, Martin -- Sanchez-Cespedes, Montserrat -- Salvesen, Helga B -- Achter, Viktor -- Lang, Ulrich -- Bogus, Magdalena -- Schneider, Peter M -- Zander, Thomas -- Ansen, Sascha -- Hallek, Michael -- Wolf, Jurgen -- Vingron, Martin -- Yatabe, Yasushi -- Travis, William D -- Nurnberg, Peter -- Reinhardt, Christian -- Perner, Sven -- Heukamp, Lukas -- Buttner, Reinhard -- Haas, Stefan A -- Brambilla, Elisabeth -- Peifer, Martin -- Sage, Julien -- Thomas, Roman K -- 5R01CA114102-08/CA/NCI NIH HHS/ -- England -- Nature. 2015 Aug 6;524(7563):47-53. doi: 10.1038/nature14664. Epub 2015 Jul 13.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Translational Genomics, Center of Integrated Oncology Cologne-Bonn, Medical Faculty, University of Cologne, 50931 Cologne, Germany. ; Departments of Pediatrics and Genetics, Stanford University, Stanford, California 94305, USA. ; Department of Pathology and Center for Cancer Genome Discovery, University of Ulsan College of Medicine, Asan Medical Center 88, Olympic-ro 43-gil, Songpa-gu, Seoul 138-736, Korea. ; Department of Pathology, University Hospital Cologne, 50937 Cologne, Germany. ; Department of Pathology, College of Medicine, Hanyang University. 222 Wangsimniro, Seongdong-gu, Seoul 133-791, Korea. ; Vancouver General Hospital, Terry Fox laboratory, Vancouver, British Columbia V5Z 1L3, Canada. ; European Molecular Biology Laboratory, Genome Biology Unit, 69117 Heidelberg, Germany. ; Institute of Pathology, Center of Integrated Oncology Cologne-Bonn, University Hospital of Bonn, 53127 Bonn, Germany. ; Center for Cancer Genome Discovery, University of Ulsan College of Medicine, Asan Medical Center 88, Olympic-ro 43-gil, Songpa-gu, Seoul 138-736, Korea. ; Department of Genetics, Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill, North Carolina 27599-7295, USA. ; UNC Lineberger Comprehensive Cancer Center School of Medicine, University of North Carolina at Chapel Hill, North Carolina 27599-7295, USA. ; Institute of Experimental Gene Therapy and Cancer Research, Rostock University Medical Center, 18057 Rostock, Germany. ; Department I of Internal Medicine, Center of Integrated Oncology Cologne-Bonn, University Hospital Cologne, 50937 Cologne, Germany. ; Department of Internal Medicine, University Hospital of Cologne, 50931 Cologne, Germany. ; Cologne Center for Genomics (CCG), University of Cologne, 50931 Cologne, Germany. ; 1] Cologne Center for Genomics (CCG), University of Cologne, 50931 Cologne, Germany. [2] Institute of Human Genetics, University Hospital Cologne, 50931 Cologne, Germany. ; 1] Division of Genome Biology, National Cancer Center Research Institute, Chuo-ku, Tokyo 1040045, Japan. [2] Genomics and Epigenomics of Cancer Prediction Program, Institute of Predictive and Personalized Medicine of Cancer (IMPPC), Barcelona 08916, Spain. ; Division of Genome Biology, National Cancer Center Research Institute, Chuo-ku, Tokyo 1040045, Japan. ; Department of Pathology and Clinical Laboratories, National Cancer Center Hospital Chuo-ku, Tokyo 1040045, Japan. ; Department of Pathology, Faculty of Medicine, University of Tsukuba, Ibaraki 305-8575, Japan. ; 1] Thoraxklinik at University Hospital Heidelberg, Amalienstrasse 5, 69126 Heidelberg, Germany. [2] Translational Lung Research Center Heidelberg (TLRC-H), Member of German Center for Lung Research (DZL), Amalienstrasse 5, 69126 Heidelberg, Germany. ; Thoraxklinik at University Hospital Heidelberg, Amalienstrasse 5, 69126 Heidelberg, Germany. ; 1] Translational Lung Research Center Heidelberg (TLRC-H), Member of German Center for Lung Research (DZL), Amalienstrasse 5, 69126 Heidelberg, Germany. [2] Institute of Pathology, University of Heidelberg, Im Neuenheimer Feld 220, 69120 Heidelberg, Germany. ; Institute of Pathology, Jena University Hospital, Friedrich-Schiller-University, 07743 Jena, Germany. ; Institute of Surgical Pathology, University Hospital Zurich, 8091 Zurich, Switzerland. ; Department of Oncology, University of Ulsan College of Medicine, Asan Medical Center, 88, Olympic-ro 43-gil, Songpa-gu, Seoul 138-736, Korea. ; Department of Thoracic and Cardiovascular Surgery, University of Ulsan College of Medicine, Asan Medical Center, 88, Olympic-ro 43-gil, Songpa-gu, Seoul 138-736, Korea. ; Thoracic Program, Vanderbilt-Ingram Cancer Center PRB 640, 2220 Pierce Avenue, Nashville, Tennessee 37232, USA. ; University Hospital of Pulmonology, Clinical Center of Serbia, Medical School, University of Belgrade, 11000 Belgrade, Serbia. ; Department of Surgery, St. Vincent's Hospital, Peter MacCallum Cancer Centre, 3065 Melbourne, Victoria, Australia. ; Department of Pathology, St. Vincent's Hospital, Peter MacCallum Cancer Centre, 3065 Melbourne, Victoria, Australia. ; Department of Haematology and Medical Oncology, Peter MacCallum Cancer Centre, 3065 Melbourne, Victoria, Australia. ; Asklepios Biobank fur Lungenerkrankungen, Comprehensive Pneumology Center Munich, Member of the German Center for Lung Research (DZL), Asklepios Fachkliniken Munchen-Gauting 82131, Germany. ; Laboratory of Oncology, IRCCS Casa Sollievo della Sofferenza, Viale Cappuccini, 71013 San Giovanni, Rotondo, Italy. ; Roy Castle Lung Cancer Research Programme, Department of Molecular and Clinical Cancer Medicine, Institute of Translational Medicine, The University of Liverpool Cancer Research Centre, 200 London Road, L69 3GA Liverpool, UK. ; University of Zagreb, School of Medicine, Department for Respiratory Diseases Jordanovac, University Hospital Center Zagreb, 10000 Zagreb, Croatia. ; Laboratory for Translational Medicine, Rudjer Boskovic Institute, 10000 Zagreb, Croatia. ; Charite Comprehensive Cancer Center, Charite Campus Mitte, 10115 Berlin, Germany. ; Tumor Genomics Unit, Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS - Istituto Nazionale Tumori, Via Venezian 1, 20133 Milan, Italy. ; Thoracic Surgery Unit, Department of Surgery, Fondazione IRCCS Istituto Nazionale Tumori, 20133 Milan, Italy. ; 1] Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, N-0424 Oslo, Norway. [2] Department of Oncology, Norwegian Radium Hospital, Oslo University Hospital, N-0310 Oslo, Norway. ; Department of Pathology, Norwegian Radium Hospital, Oslo University Hospital, N-0310 Oslo, Norway. ; Department of Pathology, VU University Medical Center, 1007 MB Amsterdam, The Netherlands. ; 1] West German Cancer Center, Department of Medical Oncology, University Hospital Essen, 45147 Essen, Germany. [2] German Cancer Consortium (DKTK), 69120 Heidelberg, Germany. ; Departments of Immunology, Genetics and Pathology, and Medical Sciences, Respiratory, Allergy and Sleep Research, Uppsala University, 75185 Uppsala, Sweden. ; Genes and Cancer Group, Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), 08908 Hospitalet de Llobregat, Barcelona, Spain. ; 1] Department of Clinical Science, Center for Cancer Biomarkers, University of Bergen, N-5058 Bergen, Norway. [2] Department of Gynecology and Obstetrics, Haukeland University Hospital, N-5058 Bergen, Norway. ; Computing Center, University of Cologne, 50931 Cologne, Germany. ; 1] Computing Center, University of Cologne, 50931 Cologne, Germany. [2] Department of Informatics, University of Cologne, 50931 Cologne, Germany. ; Institute of Legal Medicine, University of Cologne, 50823 Cologne, Germany. ; Gastrointestinal Cancer Group Cologne, Center of Integrated Oncology Cologne-Bonn, Department I for Internal Medicine, University Hospital of Cologne, 50937 Cologne, Germany. ; 1] Department I of Internal Medicine, Center of Integrated Oncology Cologne-Bonn, University Hospital Cologne, 50937 Cologne, Germany. [2] Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, 50931 Cologne, Germany. ; Computational Molecular Biology Group, Max Planck Institute for Molecular Genetics, 14195 Berlin, Germany. ; Department of Pathology and Molecular Diagnostics, Aichi Cancer Center, 464-8681 Nagoya, Japan. ; Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York 10065, USA. ; 1] Cologne Center for Genomics (CCG), University of Cologne, 50931 Cologne, Germany. [2] Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, 50931 Cologne, Germany. [3] Center for Molecular Medicine Cologne (CMMC), University of Cologne, 50931 Cologne, Germany. ; Department of Pathology, CHU Grenoble INSERM U823, University Joseph Fourier, Institute Albert Bonniot 38043, CS10217 Grenoble, France. ; 1] Department of Translational Genomics, Center of Integrated Oncology Cologne-Bonn, Medical Faculty, University of Cologne, 50931 Cologne, Germany. [2] Center for Molecular Medicine Cologne (CMMC), University of Cologne, 50931 Cologne, Germany. ; 1] Department of Translational Genomics, Center of Integrated Oncology Cologne-Bonn, Medical Faculty, University of Cologne, 50931 Cologne, Germany. [2] Department of Pathology, University Hospital Cologne, 50937 Cologne, Germany.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26168399" target="_blank"〉PubMed〈/a〉
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 5
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    German Medical Science GMS Publishing House; Düsseldorf
    In:  83. Jahresversammlung der Deutschen Gesellschaft für Hals-Nasen-Ohren-Heilkunde, Kopf- und Hals-Chirurgie; 20120516-20120520; Mainz; DOC12hnod302 /20120404/
    Publication Date: 2012-04-05
    Keywords: ddc: 610
    Language: German
    Type: conferenceObject
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  • 6
    Keywords: GENE ; neuroblastoma ; ENHANCERS ; LANDSCAPE ; TERT REARRANGEMENTS
    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.
    Type of Publication: Journal article published
    PubMed ID: 26466568
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  • 7
    Keywords: carcinoma ; IN-VIVO ; PATHWAY ; GENES ; MUTATIONS ; MOUSE MODEL ; C-KIT ; CYCLE ARREST ; NEUROENDOCRINE TUMORS ; NOTCH
    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, TP73Deltaex2/3. 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.
    Type of Publication: Journal article published
    PubMed ID: 26168399
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  • 8
    Abstract: Purpose: The 8p12-p11 locus is frequently amplified in squamous cell lung cancer (SQLC); the receptor tyrosine kinase fibroblast growth factor receptor 1 (FGFR1) being one of the most prominent targets of this amplification. Thus, small molecules inhibiting FGFRs have been employed to treat FGFR1-amplified SQLC. However, only about 11% of such FGFR1-amplified tumors respond to single-agent FGFR inhibition and several tumors exhibited insufficient tumor shrinkage, compatible with the existence of drug-resistant tumor cells.Experimental Design: To investigate possible mechanisms of resistance to FGFR inhibition, we studied the lung cancer cell lines DMS114 and H1581. Both cell lines are highly sensitive to three different FGFR inhibitors, but exhibit sustained residual cellular viability under treatment, indicating a subpopulation of existing drug-resistant cells. We isolated these subpopulations by treating the cells with constant high doses of FGFR inhibitors.Results: The FGFR inhibitor-resistant cells were cross-resistant and characterized by sustained MAPK pathway activation. In drug-resistant H1581 cells, we identified NRAS amplification and DUSP6 deletion, leading to MAPK pathway reactivation. Furthermore, we detected subclonal NRAS amplifications in 3 of 20 (15%) primary human FGFR1-amplified SQLC specimens. In contrast, drug-resistant DMS114 cells exhibited transcriptional upregulation of MET that drove MAPK pathway reactivation. As a consequence, we demonstrate that rational combination therapies resensitize resistant cells to treatment with FGFR inhibitors.Conclusions: We provide evidence for the existence of diverse mechanisms of primary drug resistance in FGFR1-amplified lung cancer and provide a rational strategy to improve FGFR inhibitor therapies by combination treatment. Clin Cancer Res; 23(18); 5527-36. (c)2017 AACR.
    Type of Publication: Journal article published
    PubMed ID: 28630215
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  • 9
    Abstract: Oxytocin (OXT)-mediated behavioral responses to social and stressful cues have extensively been studied in male rodents. Here, we investigated the capacity of brain OXT receptor (OXTR) signaling in the lateral septum (LS) to prevent social fear expression in female mice using the social-fear-conditioning paradigm. Utilizing the activated OXT system during lactation, we show that lactating mice did not express fear 24 hr after social fear conditioning. Supporting the role of OXTR signaling in the LS in attenuation of social fear, synthetic OXT infusion or overexpression of OXTR in the LS diminished social fear expression, whereas constitutive OXTR knockout severely impaired social fear extinction in virgin mice. Subsequently, both pharmacological blockade of local OXTRs in the LS and chemogenetic silencing of supraoptic nucleus OXTergic afferents to the LS increased social fear expression in lactating mice. Hence, LS-projecting OXT neurons suppress social fear in female mice.
    Type of Publication: Journal article published
    PubMed ID: 29551417
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  • 10
    Abstract: Small cell lung cancer (SCLC) patient-derived xenografts (PDX) can be generated from biopsies or circulating tumor cells (CTC), though scarcity of tissue and low efficiency of tumor growth have previously limited these approaches. Applying an established clinical-translational pipeline for tissue collection and an automated microfluidic platform for CTC enrichment, we generated 17 biopsy-derived PDXs and 17 CTC-derived PDXs in a 2-year timeframe, at 89% and 38% efficiency, respectively. Whole-exome sequencing showed that somatic alterations are stably maintained between patient tumors and PDXs. Early-passage PDXs maintain the genomic and transcriptional profiles of the founder PDX. In vivo treatment with etoposide and platinum (EP) in 30 PDX models demonstrated greater sensitivity in PDXs from EP-naive patients, and resistance to EP corresponded to increased expression of a MYC gene signature. Finally, serial CTC-derived PDXs generated from an individual patient at multiple time points accurately recapitulated the evolving drug sensitivities of that patient's disease. Collectively, this work highlights the translational potential of this strategy.Significance: Effective translational research utilizing SCLC PDX models requires both efficient generation of models from patients and fidelity of those models in representing patient tumor characteristics. We present approaches for efficient generation of PDXs from both biopsies and CTCs, and demonstrate that these models capture the mutational landscape and functional features of the donor tumors. Cancer Discov; 8(5); 600-15. (c)2018 AACR.This article is highlighted in the In This Issue feature, p. 517.
    Type of Publication: Journal article published
    PubMed ID: 29483136
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