Comprehensive genomic profiles of small cell lung cancer

Julie George, Jing Shan Lim, Se Jin Jang, Yupeng Cun, Luka Ozretić, Gu Kong, Frauke Leenders, Xin Lu, Lynnette Fernández-Cuesta, Graziella Bosco, Christian Müller, Ilona Dahmen, Nadine S. Jahchan, Kwon-Sik Park, Dian Yang, Anthony N. Karnezis, Dedeepya Vaka, Angela Torres, Maia Segura Wang, Jan O. Korbel, Roopika Menon, Sung-Min Chun, Deokhoon Kim, Matt Wilkerson, Neil Hayes, David Engelmann, Brigitte Pützer, Marc Bos, Sebastian Michels, Ignacija Vlasic, Danila Seidel, Berit Pinther, Philipp Schaub, Christian Becker, Janine Altmüller, Jun Yokota, Takashi Kohno, Reika Iwakawa, Koji Tsuta, Masayuki Noguchi, Thomas Muley, Hans Hoffmann, Philipp A. Schnabel, Iver Petersen, Yuan Chen, Alex Soltermann, Verena Tischler, Chang-min Choi, Yong-Hee Kim, Pierre P. Massion, Yong Zou, Dragana Jovanovic, Milica Kontic, Gavin M. Wright, Prudence A. Russell, Benjamin Solomon, Ina Koch, Michael Lindner, Lucia A. Muscarella, Annamaria la Torre, John K. Field, Marko Jakopovic, Jelena Knezevic, Esmeralda Castaños-Vélez, Luca Roz, Ugo Pastorino, Odd-Terje Brustugun, Marius Lund-Iversen, Erik Thunnissen, Jens Köhler, Martin Schuler, Johan Botling, Martin Sandelin, Montserrat Sanchez-Cespedes, Helga B. Salvesen, Viktor Achter, Ulrich Lang, Magdalena Bogus, Peter M. Schneider, Thomas Zander, Sascha Ansén, Michael Hallek, Jürgen Wolf, Martin Vingron, Yasushi Yatabe, William D. Travis, Peter Nürnberg, Christian Reinhardt, Sven Perner, Lukas Heukamp, Reinhard Büttner, Stefan A. Haas, Elisabeth Brambilla, Martin Peifer (), Julien Sage () and Roman K. Thomas ()
Additional contact information
Julie George: Center of Integrated Oncology Cologne–Bonn, Medical Faculty, University of Cologne
Jing Shan Lim: Stanford University
Se Jin Jang: University of Ulsan College of Medicine, Asan Medical Center
Yupeng Cun: Center of Integrated Oncology Cologne–Bonn, Medical Faculty, University of Cologne
Luka Ozretić: University Hospital Cologne
Gu Kong: College of Medicine, Hanyang University
Frauke Leenders: Center of Integrated Oncology Cologne–Bonn, Medical Faculty, University of Cologne
Xin Lu: Center of Integrated Oncology Cologne–Bonn, Medical Faculty, University of Cologne
Lynnette Fernández-Cuesta: Center of Integrated Oncology Cologne–Bonn, Medical Faculty, University of Cologne
Graziella Bosco: Center of Integrated Oncology Cologne–Bonn, Medical Faculty, University of Cologne
Christian Müller: Center of Integrated Oncology Cologne–Bonn, Medical Faculty, University of Cologne
Ilona Dahmen: Center of Integrated Oncology Cologne–Bonn, Medical Faculty, University of Cologne
Nadine S. Jahchan: Stanford University
Kwon-Sik Park: Stanford University
Dian Yang: Stanford University
Anthony N. Karnezis: Vancouver General Hospital, Terry Fox laboratory
Dedeepya Vaka: Stanford University
Angela Torres: Stanford University
Maia Segura Wang: European Molecular Biology Laboratory, Genome Biology Unit
Jan O. Korbel: European Molecular Biology Laboratory, Genome Biology Unit
Roopika Menon: Institute of Pathology, Center of Integrated Oncology Cologne–Bonn, University Hospital of Bonn
Sung-Min Chun: University of Ulsan College of Medicine, Asan Medical Center
Deokhoon Kim: Center for Cancer Genome Discovery, University of Ulsan College of Medicine, Asan Medical Center
Matt Wilkerson: Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill
Neil Hayes: UNC Lineberger Comprehensive Cancer Center School of Medicine, University of North Carolina at Chapel Hill
David Engelmann: Institute of Experimental Gene Therapy and Cancer Research, Rostock University Medical Center
Brigitte Pützer: Institute of Experimental Gene Therapy and Cancer Research, Rostock University Medical Center
Marc Bos: Center of Integrated Oncology Cologne–Bonn, Medical Faculty, University of Cologne
Sebastian Michels: Center of Integrated Oncology Cologne-Bonn, University Hospital Cologne
Ignacija Vlasic: University Hospital of Cologne
Danila Seidel: Center of Integrated Oncology Cologne–Bonn, Medical Faculty, University of Cologne
Berit Pinther: Center of Integrated Oncology Cologne–Bonn, Medical Faculty, University of Cologne
Philipp Schaub: Center of Integrated Oncology Cologne–Bonn, Medical Faculty, University of Cologne
Christian Becker: Cologne Center for Genomics (CCG), University of Cologne
Janine Altmüller: Cologne Center for Genomics (CCG), University of Cologne
Jun Yokota: National Cancer Center Research Institute, Chuo-ku
Takashi Kohno: National Cancer Center Research Institute, Chuo-ku
Reika Iwakawa: National Cancer Center Research Institute, Chuo-ku
Koji Tsuta: National Cancer Center Hospital Chuo-ku
Masayuki Noguchi: Faculty of Medicine, University of Tsukuba
Thomas Muley: Thoraxklinik at University Hospital Heidelberg
Hans Hoffmann: Thoraxklinik at University Hospital Heidelberg
Philipp A. Schnabel: Translational Lung Research Center Heidelberg (TLRC-H), Member of German Center for Lung Research (DZL)
Iver Petersen: Institute of Pathology, Jena University Hospital, Friedrich-Schiller-University
Yuan Chen: Institute of Pathology, Jena University Hospital, Friedrich-Schiller-University
Alex Soltermann: Institute of Surgical Pathology, University Hospital Zürich
Verena Tischler: Institute of Surgical Pathology, University Hospital Zürich
Chang-min Choi: University of Ulsan College of Medicine, Asan Medical Center
Yong-Hee Kim: University of Ulsan College of Medicine, Asan Medical Center
Pierre P. Massion: Thoracic Program, Vanderbilt-Ingram Cancer Center PRB 640
Yong Zou: Thoracic Program, Vanderbilt-Ingram Cancer Center PRB 640
Dragana Jovanovic: University Hospital of Pulmonology, Clinical Center of Serbia, Medical School, University of Belgrade
Milica Kontic: University Hospital of Pulmonology, Clinical Center of Serbia, Medical School, University of Belgrade
Gavin M. Wright: St. Vincent’s Hospital, Peter MacCallum Cancer Centre
Prudence A. Russell: St. Vincent’s Hospital, Peter MacCallum Cancer Centre
Benjamin Solomon: Peter MacCallum Cancer Centre
Ina Koch: Asklepios Biobank für Lungenerkrankungen, Comprehensive Pneumology Center Munich, Member of the German Center for Lung Research (DZL), Asklepios Fachkliniken München-Gauting
Michael Lindner: Asklepios Biobank für Lungenerkrankungen, Comprehensive Pneumology Center Munich, Member of the German Center for Lung Research (DZL), Asklepios Fachkliniken München-Gauting
Lucia A. Muscarella: Laboratory of Oncology, IRCCS Casa Sollievo della Sofferenza, Viale Cappuccini
Annamaria la Torre: Laboratory of Oncology, IRCCS Casa Sollievo della Sofferenza, Viale Cappuccini
John K. Field: Roy Castle Lung Cancer Research Programme, Institute of Translational Medicine, The University of Liverpool Cancer Research Centre
Marko Jakopovic: University of Zagreb, School of Medicine, University Hospital Center Zagreb
Jelena Knezevic: Laboratory for Translational Medicine, Rudjer Boskovic Institute
Esmeralda Castaños-Vélez: Charité Comprehensive Cancer Center, Charité Campus Mitte
Luca Roz: Tumor Genomics Unit, Fondazione IRCCS — Istituto Nazionale Tumori
Ugo Pastorino: Thoracic Surgery Unit, Fondazione IRCCS Istituto Nazionale Tumori
Odd-Terje Brustugun: Institute of Clinical Medicine, Faculty of Medicine, University of Oslo
Marius Lund-Iversen: Norwegian Radium Hospital, Oslo University Hospital
Erik Thunnissen: VU University Medical Center
Jens Köhler: West German Cancer Center, University Hospital Essen
Martin Schuler: West German Cancer Center, University Hospital Essen
Johan Botling: Genetics and Pathology, and Medical Sciences, Respiratory, Allergy and Sleep Research, Uppsala University
Martin Sandelin: Genetics and Pathology, and Medical Sciences, Respiratory, Allergy and Sleep Research, Uppsala University
Montserrat Sanchez-Cespedes: Genes and Cancer Group, Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL)
Helga B. Salvesen: Center for Cancer Biomarkers, University of Bergen
Viktor Achter: Computing Center, University of Cologne
Ulrich Lang: Computing Center, University of Cologne
Magdalena Bogus: Institute of Legal Medicine, University of Cologne
Peter M. Schneider: Institute of Legal Medicine, University of Cologne
Thomas Zander: Gastrointestinal Cancer Group Cologne, Center of Integrated Oncology Cologne–Bonn, University Hospital of Cologne
Sascha Ansén: Center of Integrated Oncology Cologne-Bonn, University Hospital Cologne
Michael Hallek: Center of Integrated Oncology Cologne-Bonn, University Hospital Cologne
Jürgen Wolf: Center of Integrated Oncology Cologne-Bonn, University Hospital Cologne
Martin Vingron: Computational Molecular Biology Group, Max Planck Institute for Molecular Genetics
Yasushi Yatabe: Aichi Cancer Center
William D. Travis: Memorial Sloan-Kettering Cancer Center
Peter Nürnberg: Cologne Center for Genomics (CCG), University of Cologne
Christian Reinhardt: University Hospital of Cologne
Sven Perner: Center for Cancer Genome Discovery, University of Ulsan College of Medicine, Asan Medical Center
Lukas Heukamp: University Hospital Cologne
Reinhard Büttner: University Hospital Cologne
Stefan A. Haas: Computational Molecular Biology Group, Max Planck Institute for Molecular Genetics
Elisabeth Brambilla: CHU Grenoble INSERM U823, University Joseph Fourier, Institute Albert Bonniot 38043
Martin Peifer: Center of Integrated Oncology Cologne–Bonn, Medical Faculty, University of Cologne
Julien Sage: Stanford University
Roman K. Thomas: Center of Integrated Oncology Cologne–Bonn, Medical Faculty, University of Cologne

Nature, 2015, vol. 524, issue 7563, 47-53

Abstract: 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.

Date: 2015
References: Add references at CitEc
Citations: View citations in EconPapers (1)

Downloads: (external link)
https://www.nature.com/articles/nature14664 Abstract (text/html)
Access to the full text of the articles in this series is restricted.

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:nature:v:524:y:2015:i:7563:d:10.1038_nature14664

Ordering information: This journal article can be ordered from
https://www.nature.com/

DOI: 10.1038/nature14664

Access Statistics for this article

Nature is currently edited by Magdalena Skipper

More articles in Nature from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().