Comprehensive genomic profiles of small cell lung cancer

Item Type:	Article
Title:	Comprehensive genomic profiles of small cell lung cancer
Creators Name:	George, J. and Lim, J.S. and Jang, S.J. and Cun, Y. and Ozretić, L. and Kong, G. and Leenders, F. and Lu, X. and Fernández-Cuesta, L. and Bosco, G. and Müller, C. and Dahmen, I. and Jahchan, N.S. and Park, K.S. and Yang, D. and Karnezis, A.N. and Vaka, D. and Torres, A. and Wang, M.S. and Korbel, J.O. and Menon, R. and Chun, S.M. and Kim, D. and Wilkerson, M. and Hayes, N. and Engelmann, D. and Pützer, B. and Bos, M. and Michels, S. and Vlasic, I. and Seidel, D. and Pinther, B. and Schaub, P. and Becker, C. and Altmüller, J. and Yokota, J. and Kohno, T. and Iwakawa, R. and Tsuta, K. and Noguchi, M. and Muley, T. and Hoffmann, H. and Schnabel, P.A. and Petersen, I. and Chen, Y. and Soltermann, A. and Tischler, V. and Choi, C.M. and Kim, Y.H. and Massion, P.P. and Zou, Y. and Jovanovic, D. and Kontic, M. and Wright, G.M. and Russell, P.A. and Solomon, B. and Koch, I. and Lindner, M. and Muscarella, L.A. and la Torre, A. and Field, J.K. and Jakopovic, M. and Knezevic, J. and Castaños-Vélez, E. and Roz, L. and Pastorino, U. and Brustugun, O.T. and Lund-Iversen, M. and Thunnissen, E. and Köhler, J. and Schuler, M. and Botling, J. and Sandelin, M. and Sanchez-Cespedes, M. and Salvesen, H.B. and Achter, V. and Lang, U. and Bogus, M. and Schneider, P.M. and Zander, T. and Ansén, S. and Hallek, M. and Wolf, J. and Vingron, M. and Yatabe, Y. and Travis, W.D. and Nürnberg, P. and Reinhardt, C. and Perner, S. and Heukamp, L. and Büttner, R. and Haas, S.A. and Brambilla, E. and Peifer, M. and Sage, J. and Thomas, R.K.
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.
Keywords:	Alleles, Animal Disease Models, Chromosome Breakpoints, Cyclin D1, DNA-Binding Proteins, Gene Expression Profiling, Genomics, Human Genome, Lung Neoplasms, Mutation, Neurosecretory Systems, Notch Receptors, Nuclear Proteins, Retinoblastoma Protein, Signal Transduction, Small Cell Lung Carcinoma, Tumor Cell Line, Tumor Protein p73, Tumor Suppressor Protein p53, Tumor Suppressor Proteins, Animals, Mice
Source:	Nature
ISSN:	0028-0836
Publisher:	Nature Publishing Group
Volume:	524
Number:	7563
Page Range:	47-53
Date:	6 August 2015
Additional Information:	Copyright © 2015 Macmillan Publishers Limited. All rights reserved
Official Publication:	https://doi.org/10.1038/nature14664
External Fulltext:	View full text on PubMed Central
PubMed:	View item in PubMed

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