Comprehensive genomic profiles of small cell lung cancer

Julie George, Jing Shan Lim, Se Jin Jang, Yupeng Cun, Luka Ozretia, Gu Kong, Frauke Leenders, Xin Lu, Lynnette Fernández-Cuesta, Graziella Bosco, Christian Müller, Ilona Dahmen, Nadine S. Jahchan, Kwon Sik Park, Dian Yang, Anthony Karnezis, Dedeepya Vaka, Angela Torres, Maia Segura Wang, Jan O. KorbelRoopika 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, Roman K. Thomas

Research output: Contribution to journalArticle

643 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)47-53
Number of pages7
JournalNature
Volume524
Issue number7563
DOIs
StatePublished - Aug 6 2015
Externally publishedYes

ASJC Scopus subject areas

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    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., Vaka, D., Torres, A., Wang, M. S., ... Thomas, R. K. (2015). Comprehensive genomic profiles of small cell lung cancer. Nature, 524(7563), 47-53. https://doi.org/10.1038/nature14664