Résumé
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.
| langue originale | Anglais |
|---|---|
| Pages (de - à) | 1104-1110 |
| Nombre de pages | 7 |
| journal | Nature Genetics |
| Volume | 44 |
| Numéro de publication | 10 |
| Les DOIs | |
| état | Publié - 1 oct. 2012 |
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Dans: Nature Genetics, Vol 44, Numéro 10, 01.10.2012, p. 1104-1110.
Résultats de recherche: Contribution à un journal › Article › Revue par des pairs
TY - JOUR
T1 - Integrative genome analyses identify key somatic driver mutations of small-cell lung cancer
AU - Peifer, Martin
AU - Fernández-Cuesta, Lynnette
AU - Sos, Martin L.
AU - George, Julie
AU - Seidel, Danila
AU - Kasper, Lawryn H.
AU - Plenker, Dennis
AU - Leenders, Frauke
AU - Sun, Ruping
AU - Zander, Thomas
AU - Menon, Roopika
AU - Koker, Mirjam
AU - Dahmen, Ilona
AU - Müller, Christian
AU - Di Cerbo, Vincenzo
AU - Schildhaus, Hans Ulrich
AU - Altmüller, Janine
AU - Baessmann, Ingelore
AU - Becker, Christian
AU - De Wilde, Bram
AU - Vandesompele, Jo
AU - Böhm, Diana
AU - Ansén, Sascha
AU - Gabler, Franziska
AU - Wilkening, Ines
AU - Heynck, Stefanie
AU - Heuckmann, Johannes M.
AU - Lu, Xin
AU - Carter, Scott L.
AU - Cibulskis, Kristian
AU - Banerji, Shantanu
AU - Getz, Gad
AU - Park, Kwon Sik
AU - Rauh, Daniel
AU - Grütter, Christian
AU - Fischer, Matthias
AU - Pasqualucci, Laura
AU - Wright, Gavin
AU - Wainer, Zoe
AU - Russell, Prudence
AU - Petersen, Iver
AU - Chen, Yuan
AU - Stoelben, Erich
AU - Ludwig, Corinna
AU - Schnabel, Philipp
AU - Hoffmann, Hans
AU - Muley, Thomas
AU - Brockmann, Michael
AU - Engel-Riedel, Walburga
AU - Muscarella, Lucia A.
AU - Fazio, Vito M.
AU - Groen, Harry
AU - Timens, Wim
AU - Sietsma, Hannie
AU - Thunnissen, Erik
AU - Smit, Egber
AU - Heideman, Daniëlle A.M.
AU - Snijders, Peter J.F.
AU - Cappuzzo, Federico
AU - Ligorio, Claudia
AU - Damiani, Stefania
AU - Field, John
AU - Solberg, Steinar
AU - Brustugun, Odd Terje
AU - Lund-Iversen, Marius
AU - Sänger, Jörg
AU - Clement, Joachim H.
AU - Soltermann, Alex
AU - Moch, Holger
AU - Weder, Walter
AU - Solomon, Benjamin
AU - Soria, Jean Charles
AU - Validire, Pierre
AU - Besse, Benjamin
AU - Brambilla, Elisabeth
AU - Brambilla, Christian
AU - Lantuejoul, Sylvie
AU - Lorimier, Philippe
AU - Schneider, Peter M.
AU - Hallek, Michael
AU - Pao, William
AU - Meyerson, Matthew
AU - Sage, Julien
AU - Shendure, Jay
AU - Schneider, Robert
AU - Büttner, Reinhard
AU - Wolf, Jürgen
AU - Nürnberg, Peter
AU - Perner, Sven
AU - Heukamp, Lukas C.
AU - Brindle, Paul K.
AU - Haas, Stefan
AU - Thomas, Roman K.
N1 - 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).
PY - 2012/10/1
Y1 - 2012/10/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84866851740&partnerID=8YFLogxK
U2 - 10.1038/ng.2396
DO - 10.1038/ng.2396
M3 - Article
C2 - 22941188
AN - SCOPUS:84866851740
SN - 1061-4036
VL - 44
SP - 1104
EP - 1110
JO - Nature Genetics
JF - Nature Genetics
IS - 10
ER -