Integrative genome analyses identify key somatic driver mutations of small-cell lung cancer

Martin Peifer, Lynnette Fernández-Cuesta, Martin L. Sos, Julie George, Danila Seidel, Lawryn H. Kasper, Dennis Plenker, Frauke Leenders, Ruping Sun, Thomas Zander, Roopika Menon, Mirjam Koker, Ilona Dahmen, Christian Müller, Vincenzo Di Cerbo, Hans Ulrich Schildhaus, Janine Altmüller, Ingelore Baessmann, Christian Becker, Bram De WildeJo Vandesompele, Diana Böhm, Sascha Ansén, Franziska Gabler, Ines Wilkening, Stefanie Heynck, Johannes M. Heuckmann, Xin Lu, Scott L. Carter, Kristian Cibulskis, Shantanu Banerji, Gad Getz, Kwon Sik Park, Daniel Rauh, Christian Grütter, Matthias Fischer, Laura Pasqualucci, Gavin Wright, Zoe Wainer, Prudence Russell, Iver Petersen, Yuan Chen, Erich Stoelben, Corinna Ludwig, Philipp Schnabel, Hans Hoffmann, Thomas Muley, Michael Brockmann, Walburga Engel-Riedel, Lucia A. Muscarella, Vito M. Fazio, Harry Groen, Wim Timens, Hannie Sietsma, Erik Thunnissen, Egber Smit, Daniëlle A.M. Heideman, Peter J.F. Snijders, Federico Cappuzzo, Claudia Ligorio, Stefania Damiani, John Field, Steinar Solberg, Odd Terje Brustugun, Marius Lund-Iversen, Jörg Sänger, Joachim H. Clement, Alex Soltermann, Holger Moch, Walter Weder, Benjamin Solomon, Jean Charles Soria, Pierre Validire, Benjamin Besse, Elisabeth Brambilla, Christian Brambilla, Sylvie Lantuejoul, Philippe Lorimier, Peter M. Schneider, Michael Hallek, William Pao, Matthew Meyerson, Julien Sage, Jay Shendure, Robert Schneider, Reinhard Büttner, Jürgen Wolf, Peter Nürnberg, Sven Perner, Lukas C. Heukamp, Paul K. Brindle, Stefan Haas, Roman K. Thomas

Research output: Contribution to journalArticlepeer-review

755 Scopus citations

Abstract

Small-cell lung cancer (SCLC) is an aggressive lung tumor subtype with poor prognosis. We sequenced 29 SCLC exomes, 2 genomes and 15 transcriptomes and found an extremely high mutation rate of 7.4 ± 1 protein-changing mutations per million base pairs. Therefore, we conducted integrated analyses of the various data sets to identify pathogenetically relevant mutated genes. In all cases, we found evidence for inactivation of TP53 and RB1 and identified recurrent mutations in the CREBBP, EP300 and MLL genes that encode histone modifiers. Furthermore, we observed mutations in PTEN, SLIT2 and EPHA7, as well as focal amplifications of the FGFR1 tyrosine kinase gene. Finally, we detected many of the alterations found in humans in SCLC tumors from Tp53 and Rb1 double knockout mice. Our study implicates histone modification as a major feature of SCLC, reveals potentially therapeutically tractable genomic alterations and provides a generalizable framework for the identification of biologically relevant genes in the context of high mutational background.

Original languageEnglish (US)
Pages (from-to)1104-1110
Number of pages7
JournalNature Genetics
Volume44
Issue number10
DOIs
StatePublished - Oct 2012

Bibliographical note

Funding Information:
We are indebted to the individuals donating their tumor specimens as part of the Clinical Lung Cancer Genome Project initiative. Additional biospecimens for this study were obtained from the Victorian Cancer Biobank (Melbourne, Australia). The Institutional Review Board (IRB) of each participating institution approved collection and use of all specimens in this study. We also thank our colleagues at The Cancer Genome Atlas Research Network (TCGA) and A.L. Kung for invaluable discussion and many helpful comments. This work was supported by the German Ministry of Science and Education (BMBF) as part of the NGFNplus program (grant 01GS08100 to R.K.T. and 01GS08101 to J.W. and P.N.), by the Max Planck Society (M.I.F.A.NEUR8061 to R.K.T.), by the Deutsche Forschungsgemeinschaft (DFG) through SFB832 (TP6 to R.K.T. and TP5 and Z1 to L.C.H. and R.B.) and TH1386/3-1 (to R.K.T. and M.L.S.), by the European Union’s Framework Programme CURELUNG (HEALTH-F2-2010-258677 to R.K.T., J.F., E.B., C. Brambilla, S.L., B.B. and J.W.), by Stand Up To Cancer–American Association for Cancer Research Innovative Research Grant (SU2C-AACR-IR60109 to R.K.T. and W.P.), by the Behrens-Weise Foundation (to R.K.T.) and by an anonymous foundation to R.K.T. M.L.S. is a fellow of the International Association for the Study of Lung Cancer (IASLC). P.K.B. and L.H.K. thank the St. Jude Cell and Tissue Imaging facility and acknowledge support from the US National Institutes of Health (NIH) Cancer Center (grant P30 CA021765) and the American Lebanese Syrian Associated Charities of St. Jude Children’s Research Hospital. F.C. was supported by Associazione Italiana Ricerca sul Cancro (AIRC, grant IG 9425).

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