Publication

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

Peifer, M., Fernandez-Cuesta, L., Sos, M. L., George, J., Seidel, D., Kasper, L. H., Plenker, D., Leenders, F., Sun, R., Zander, T., Menon, R., Koker, M., Dahmen, I., Mueller, C., Di Cerbo, V., Schildhaus, H-U., Altmueller, J., Baessmann, I., Becker, C., de Wilde, B., Vandesompele, J., Boehm, D., Ansen, S., Gabler, F., Wilkening, I., Heynck, S., Heuckmann, J. M., Lu, X., Carter, S. L., Cibulskis, K., Banerji, S., Getz, G., Park, K-S., Rauh, D., Gruetter, C., Fischer, M., Pasqualucci, L., Wright, G., Wainer, Z., Russell, P., Petersen, I., Chen, Y., Stoelben, E., Ludwig, C., Schnabel, P., Hoffmann, H., Muley, T., Brockmann, M., Engel-Riedel, W., Muscarella, L. A., Fazio, V. M., Groen, H., Timens, W., Sietsma, H., Thunnissen, E., Smit, E., Heideman, D. A. M., Snijders, P. J. F., Cappuzzo, F., Ligorio, C., Damiani, S., Field, J., Solberg, S., Brustugun, O. T., Lund-Iversen, M., Saenger, J., Clement, J. H., Soltermann, A., Moch, H., Weder, W., Solomon, B., Soria, J-C., Validire, P., Besse, B., Brambilla, E., Brambilla, C., Lantuejoul, S., Lorimier, P., Schneider, P. M., Hallek, M., Pao, W., Meyerson, M., Sage, J., Shendure, J., Schneider, R., Buettner, R., Wolf, J., Nuernberg, P., Perner, S., Heukamp, L. C., Brindle, P. K., Haas, S. & Thomas, R. K., Oct-2012, In : Nature Genetics. 44, 10, p. 1104-+ 9 p.

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DOI

  • Martin Peifer
  • Lynnette Fernandez-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 Mueller
  • Vincenzo Di Cerbo
  • Hans-Ulrich Schildhaus
  • Janine Altmueller
  • Ingelore Baessmann
  • Christian Becker
  • Bram de Wilde
  • Jo Vandesompele
  • Diana Boehm
  • Sascha Ansen
  • 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 Gruetter
  • 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
  • Egbert Smit
  • Danielle A. M. Heideman
  • Peter J. F. Snijders
  • Federico Cappuzzo
  • Claudia Ligorio
  • Stefania Damiani
  • John Field
  • Steinar Solberg
  • Odd Terje Brustugun
  • Marius Lund-Iversen
  • Joerg Saenger
  • 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 Buettner
  • Juergen Wolf
  • Peter Nuernberg
  • Sven Perner
  • Lukas C. Heukamp
  • Paul K. Brindle
  • Stefan Haas
  • Roman K. Thomas

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.

Original languageEnglish
Pages (from-to)1104-+
Number of pages9
JournalNature Genetics
Volume44
Issue number10
Publication statusPublished - Oct-2012

    Keywords

  • ACUTE LYMPHOBLASTIC-LEUKEMIA, MOUSE MODEL, NEUROENDOCRINE TUMORS, FREQUENT MUTATION, PROSTATE-CANCER, EGFR MUTATIONS, P53 REGULATION, EPH-RECEPTOR, E-CADHERIN, GENE

ID: 2413095