| Authors: |
George, J.; Lim, J. S.; Jang, S. J.; Cun, Y.; Ozretia, L.; Kong, G.; Leenders, F.; Lu, X.; Fernández-Cuesta, L.; Bosco, G.; Müller, C.; Dahmen, I.; Jahchan, N. S.; Park, K. S.; Yang, D.; Karnezis, A. N.; Vaka, D.; Torres, A.; Wang, M. S.; Korbel, J. O.; Menon, R.; Chun, S. M.; Kim, D.; Wilkerson, M.; Hayes, N.; Engelmann, D.; Pützer, B.; Bos, M.; Michels, S.; Vlasic, I.; Seidel, D.; Pinther, B.; Schaub, P.; Becker, C.; Altmüller, J.; Yokota, J.; Kohno, T.; Iwakawa, R.; Tsuta, K.; Noguchi, M.; Muley, T.; Hoffmann, H.; Schnabel, P. A.; Petersen, I.; Chen, Y.; Soltermann, A.; Tischler, V.; Choi, C. M.; Kim, Y. H.; Massion, P. P.; Zou, Y.; Jovanovic, D.; Kontic, M.; Wright, G. M.; Russell, P. A.; Solomon, B.; Koch, I.; Lindner, M.; Muscarella, L. A.; La Torre, A.; Field, J. K.; Jakopovic, M.; Knezevic, J.; Castaños-Vélez, E.; Roz, L.; Pastorino, U.; Brustugun, O. T.; Lund-Iversen, M.; Thunnissen, E.; Köhler, J.; Schuler, M.; Botling, J.; Sandelin, M.; Sanchez-Cespedes, M.; Salvesen, H. B.; Achter, V.; Lang, U.; Bogus, M.; Schneider, P. M.; Zander, T.; Ansén, S.; Hallek, M.; Wolf, J.; Vingron, M.; Yatabe, Y.; Travis, W. D.; Nürnberg, P.; Reinhardt, C.; Perner, S.; Heukamp, L.; Büttner, R.; Haas, S. A.; Brambilla, E.; Peifer, M.; Sage, J.; Thomas, R. K. |
| Article Title: |
Comprehensive genomic profiles of small cell lung cancer |
| 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, TP73I "ex2/3. 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. © 2015 Macmillan Publishers Limited. All rights reserved. |
| Keywords: |
controlled study; human tissue; unclassified drug; gene mutation; human cell; major clinical study; nonhuman; mouse; mus; gene expression; animal experiment; animal model; wild type; protein p53; gene rearrangement; genome; tumor suppressor protein; mutant; multigene family; small cell lung cancer; experimental model; human; male; female; priority journal; article; rb1 protein; cyclin d1 gene
|
| Journal Title: |
Nature
|
| Volume: |
524 |
| Issue: |
7563 |
| ISSN: |
0028-0836 |
| Publisher: |
Nature Publishing Group
|
| Date Published: |
2015-08-06 |
| Start Page: |
47 |
| End Page: |
53 |
| Language: |
English |
| DOI: |
10.1038/nature14664
|
| PROVIDER: |
scopus
|
| PUBMED: |
26168399
|
| PMCID: |
PMC4861069
|
| DOI/URL: |
|
| Notes: |
Export Date: 2 September 2015 -- Source: Scopus |
