1. Comprehensive genomic profiles of small cell lung cancer
- Author
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Lucia Anna Muscarella, Yong-Hee Kim, Ilona Dahmen, Marc Bos, Luka Ozretić, Dedeepya Vaka, Frauke Leenders, John K. Field, Montserrat Sanchez-Cespedes, Matthew D. Wilkerson, Gavin M. Wright, Sung-Min Chun, Viktor Achter, Lukas C. Heukamp, Danila Seidel, Prudence A. Russell, Peter Nürnberg, Philipp Schaub, Martin Peifer, David Engelmann, Nadine Jahchan, Pierre P. Massion, Roman K. Thomas, Stefan A. Haas, Peter M. Schneider, Elisabeth Brambilla, Julie George, Dian Yang, Maia Segura Wang, Christian Reinhardt, Benjamin Solomon, Anthony N. Karnezis, Koji Tsuta, Roopika Menon, Julien Sage, Dragana Jovanovic, Esmeralda Castaños-Vélez, Takashi Kohno, Ulrich Lang, Helga B. Salvesen, Xin Lu, Ángela Torres, Michael Lindner, Se Jin Jang, Milica Kontic, Hans Hoffmann, Reika Iwakawa, Reinhard Büttner, Berit Pinther, Martin Vingron, Kwon-Sik Park, Sascha Ansén, Yasushi Yatabe, Martin Schuler, Christian Müller, O.T. Brustugun, Jun Yokota, Johan Botling, Neil Hayes, Yupeng Cun, Magdalena Bogus, Deokhoon Kim, Jens Köhler, Jan O. Korbel, William D. Travis, Sebastian Michels, Jürgen Wolf, Martin Sandelin, Marius Lund-Iversen, Brigitte M. Pützer, Verena Tischler, Ina Koch, Ignacija Vlasic, Yuan Chen, Janine Altmüller, Masayuki Noguchi, Michael Hallek, Jing Shan Lim, Alex Soltermann, Lynnette Fernandez-Cuesta, Thomas Zander, Gu Kong, Christian Becker, Luca Roz, Yong Zou, Graziella Bosco, Iver Petersen, Philipp A. Schnabel, Sven Perner, Marko Jakopović, Chang-Min Choi, Jelena Knezevic, Ugo Pastorino, Thomas Muley, Annamaria la Torre, Erik Thunnissen, Pathology, and CCA - Oncogenesis
- Subjects
Male ,Lung Neoplasms ,Medizin ,Gene mutation ,medicine.disease_cause ,Retinoblastoma Protein ,Mice ,Chromosome Breakpoints ,0302 clinical medicine ,Receptors ,2.1 Biological and endogenous factors ,Cyclin D1 ,Aetiology ,Lung ,Cancer ,Genetics ,0303 health sciences ,Mutation ,Multidisciplinary ,Chromothripsis ,Tumor ,Genome ,Receptors, Notch ,Lung Cancer ,Nuclear Proteins ,Genomics ,3. Good health ,DNA-Binding Proteins ,ASCL1 ,030220 oncology & carcinogenesis ,Female ,Signal Transduction ,Human ,Notch ,General Science & Technology ,Comprehensive genomic profiles ,Small cell lung cancer ,TP53 and RB1 tumor supressors ,Notch signaling pathway ,Biology ,Article ,Cell Line ,03 medical and health sciences ,Rare Diseases ,Cell Line, Tumor ,medicine ,Animals ,Humans ,neoplasms ,Alleles ,030304 developmental biology ,Genome, Human ,Animal ,Tumor Suppressor Proteins ,Gene Expression Profiling ,Human Genome ,Rovalpituzumab tesirine ,Tumor Protein p73 ,medicine.disease ,Neurosecretory Systems ,Small Cell Lung Carcinoma ,respiratory tract diseases ,Gene expression profiling ,Disease Models, Animal ,Genòmica ,Disease Models ,Cancer research ,Càncer de pulmó ,Tumor Suppressor Protein p53 - 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.
- Published
- 2015
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