Peifer, Martin ORCID: 0000-0002-5243-5503, Fernandez-Cuesta, Lynnette ORCID: 0000-0002-0724-6703, Sos, Martin L., George, Julie, Seidel, Danila ORCID: 0000-0003-4388-3117, Kasper, Lawryn H., Plenker, Dennis, Leenders, Frauke, Sun, Ruping, Zander, Thomas, Menon, Roopika, Koker, Mirjam, Dahmen, Ilona, Mueller, Christian, Di Cerbo, Vincenzo ORCID: 0000-0002-2920-1274, Schildhaus, Hans-Ulrich, Altmueller, Janine, Baessmann, Ingelore, Becker, Christian, de Wilde, Bram, Vandesompele, Jo ORCID: 0000-0001-6274-0184, Boehm, Diana, Ansen, Sascha, Gabler, Franziska, Wilkening, Ines, Heynck, Stefanie, Heuckmann, Johannes M., Lu, Xin, Carter, Scott L., Cibulskis, Kristian, Banerji, Shantanu, Getz, Gad, Park, Kwon-Sik, Rauh, Daniel ORCID: 0000-0002-1970-7642, Gruetter, Christian, Fischer, Matthias, Pasqualucci, Laura, Wright, Gavin ORCID: 0000-0002-7000-9305, Wainer, Zoe, Russell, Prudence, Petersen, Iver, Chen, Yuan, Stoelben, Erich, Ludwig, Corinna, Schnabel, Philipp, Hoffmann, Hans, Muley, Thomas, Brockmann, Michael, Engel-Riedel, Walburga, Muscarella, Lucia A., Fazio, Vito M., Groen, Harry, Timens, Wim ORCID: 0000-0002-4146-6363, Sietsma, Hannie, Thunnissen, Erik ORCID: 0000-0001-5355-8508, Smit, Egbert, Heideman, Danielle A. M., Snijders, Peter J. F., Cappuzzo, Federico, Ligorio, Claudia, Damiani, Stefania, Field, John, Solberg, Steinar, Brustugun, Odd Terje, Lund-Iversen, Marius, Saenger, Joerg, Clement, Joachim H. ORCID: 0000-0002-6601-2456, Soltermann, Alex, Moch, Holger, Weder, Walter, Solomon, Benjamin, Soria, Jean-Charles, Validire, Pierre, Besse, Benjamin ORCID: 0000-0001-5090-8189, Brambilla, Elisabeth, Brambilla, Christian, Lantuejoul, Sylvie, Lorimier, Philippe, Schneider, Peter M. ORCID: 0000-0003-0744-2349, Hallek, Michael, Pao, William, Meyerson, Matthew ORCID: 0000-0002-9133-8108, Sage, Julien, Shendure, Jay ORCID: 0000-0002-1516-1865, Schneider, Robert, Buettner, Reinhard, Wolf, Juergen, Nuernberg, Peter, Perner, Sven, Heukamp, Lukas C., Brindle, Paul K., Haas, Stefan ORCID: 0000-0003-3418-3688 and Thomas, Roman K. (2012). Integrative genome analyses identify key somatic driver mutations of small-cell lung cancer. Nature Genet., 44 (10). S. 1104 - 1113. NEW YORK: NATURE PUBLISHING GROUP. ISSN 1546-1718

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Abstract

Small-cell lung cancer (SCLC) is an aggressive lung tumor subtype with poor prognosis(1-3). 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 mice(4). 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.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Peifer, MartinUNSPECIFIEDorcid.org/0000-0002-5243-5503UNSPECIFIED
Fernandez-Cuesta, LynnetteUNSPECIFIEDorcid.org/0000-0002-0724-6703UNSPECIFIED
Sos, Martin L.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
George, JulieUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Seidel, DanilaUNSPECIFIEDorcid.org/0000-0003-4388-3117UNSPECIFIED
Kasper, Lawryn H.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Plenker, DennisUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Leenders, FraukeUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Sun, RupingUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Zander, ThomasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Menon, RoopikaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Koker, MirjamUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Dahmen, IlonaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Mueller, ChristianUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Di Cerbo, VincenzoUNSPECIFIEDorcid.org/0000-0002-2920-1274UNSPECIFIED
Schildhaus, Hans-UlrichUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Altmueller, JanineUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Baessmann, IngeloreUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Becker, ChristianUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
de Wilde, BramUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Vandesompele, JoUNSPECIFIEDorcid.org/0000-0001-6274-0184UNSPECIFIED
Boehm, DianaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ansen, SaschaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Gabler, FranziskaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wilkening, InesUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Heynck, StefanieUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Heuckmann, Johannes M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lu, XinUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Carter, Scott L.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Cibulskis, KristianUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Banerji, ShantanuUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Getz, GadUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Park, Kwon-SikUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Rauh, DanielUNSPECIFIEDorcid.org/0000-0002-1970-7642UNSPECIFIED
Gruetter, ChristianUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Fischer, MatthiasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Pasqualucci, LauraUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wright, GavinUNSPECIFIEDorcid.org/0000-0002-7000-9305UNSPECIFIED
Wainer, ZoeUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Russell, PrudenceUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Petersen, IverUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Chen, YuanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Stoelben, ErichUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ludwig, CorinnaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schnabel, PhilippUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hoffmann, HansUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Muley, ThomasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Brockmann, MichaelUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Engel-Riedel, WalburgaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Muscarella, Lucia A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Fazio, Vito M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Groen, HarryUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Timens, WimUNSPECIFIEDorcid.org/0000-0002-4146-6363UNSPECIFIED
Sietsma, HannieUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Thunnissen, ErikUNSPECIFIEDorcid.org/0000-0001-5355-8508UNSPECIFIED
Smit, EgbertUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Heideman, Danielle A. M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Snijders, Peter J. F.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Cappuzzo, FedericoUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ligorio, ClaudiaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Damiani, StefaniaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Field, JohnUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Solberg, SteinarUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Brustugun, Odd TerjeUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lund-Iversen, MariusUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Saenger, JoergUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Clement, Joachim H.UNSPECIFIEDorcid.org/0000-0002-6601-2456UNSPECIFIED
Soltermann, AlexUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Moch, HolgerUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Weder, WalterUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Solomon, BenjaminUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Soria, Jean-CharlesUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Validire, PierreUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Besse, BenjaminUNSPECIFIEDorcid.org/0000-0001-5090-8189UNSPECIFIED
Brambilla, ElisabethUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Brambilla, ChristianUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lantuejoul, SylvieUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lorimier, PhilippeUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schneider, Peter M.UNSPECIFIEDorcid.org/0000-0003-0744-2349UNSPECIFIED
Hallek, MichaelUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Pao, WilliamUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Meyerson, MatthewUNSPECIFIEDorcid.org/0000-0002-9133-8108UNSPECIFIED
Sage, JulienUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Shendure, JayUNSPECIFIEDorcid.org/0000-0002-1516-1865UNSPECIFIED
Schneider, RobertUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Buettner, ReinhardUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wolf, JuergenUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Nuernberg, PeterUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Perner, SvenUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Heukamp, Lukas C.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Brindle, Paul K.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Haas, StefanUNSPECIFIEDorcid.org/0000-0003-3418-3688UNSPECIFIED
Thomas, Roman K.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-482550
DOI: 10.1038/ng.2396
Journal or Publication Title: Nature Genet.
Volume: 44
Number: 10
Page Range: S. 1104 - 1113
Date: 2012
Publisher: NATURE PUBLISHING GROUP
Place of Publication: NEW YORK
ISSN: 1546-1718
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
FREQUENT MUTATION; EGFR MUTATIONS; MOUSE MODEL; E-CADHERIN; GENE; P53; CBP; ACETYLATION; SIGNATURES; FUSIONSMultiple languages
Genetics & HeredityMultiple languages
URI: http://kups.ub.uni-koeln.de/id/eprint/48255

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