Portal de Periódicos da CAPES

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

2012; Nature Portfolio; Volume: 44; Issue: 10 Linguagem: Inglês

10.1038/ng.2396

1546-1718

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 Wilde, Jo Vandesompele, Diana Böhm, Sascha Ansén, Franziska Gabler, Ines Wilkening, Stefanie Heynck, Johannes M. Heuckmann, Xin Lü, 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 A. Russell, Iver Petersen, Yuan Chen, Erich Stoelben, Corinna Ludwig, Philipp A. Schnabel, Hans Hoffmann, Thomas Muley, Michael Brockmann, Walburga Engel-Riedel, Lucia Anna Muscarella, Vito Michele Fazio, Harry J.M. Groen, Wim Timens, Hannie Sietsma, Erik Thunnissen, Egbert F. Smit, Daniëlle A.M. Heideman, Peter J.F. Snijders, Federico Cappuzzo, Claudia Ligorio, Stefania Damiani, John K. 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, Élisabeth Brambilla, Christian Brambilla, Sylvie Lantuéjoul, Philippe Lorimier, Peter M. Schneider, Michael Hallek, William Pao, Matthew Meyerson, Julien Sage, Jay Shendure, Robert C. Schneider, Reinhard Büttner, Jürgen Wolf, Peter Nürnberg, Sven Perner, Lukas C. Heukamp, Paul K. Brindle, Stefan A. Haas, Roman K. Thomas,

Neuroendocrine Tumor Research Advances

Roman Thomas and colleagues report exome sequencing of 29 small-cell lung cancers (SCLCs), 2 SCLC genomes and transcriptomes of 15 SCLCs. They identify recurrent mutations in the CREBBP, EP300 and MLL genes encoding histone modifiers. They identify mutations in SLIT2 and EPHA7, which have a role in axon guidance and cell migration, and focal amplifications of FGFR1. Small-cell lung cancer (SCLC) is an aggressive lung tumor subtype with poor prognosis1,2,3. 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 mice4. 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.