Advanced search
1 file | 1.27 MB

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

(2012) NATURE GENETICS. 44(10). p.1104-1110
Author
Organization
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.
Keywords
PROSTATE-CANCER, EGFR MUTATIONS, FREQUENT MUTATION, NEUROENDOCRINE TUMORS, ACUTE LYMPHOBLASTIC-LEUKEMIA, MOUSE MODEL, P53 REGULATION, EPH-RECEPTOR, E-CADHERIN, GENE

Downloads

  • (...).pdf
    • full text
    • |
    • UGent only
    • |
    • PDF
    • |
    • 1.27 MB

Citation

Please use this url to cite or link to this publication:

Chicago
Peifer, Martin, Lynnette Fernández-Cuesta, Martin L Sos, Julie George, Danila Seidel, Lawryn H Kasper, Dennis Plenker, et al. 2012. “Integrative Genome Analyses Identify Key Somatic Driver Mutations of Small-cell Lung Cancer.” Nature Genetics 44 (10): 1104–1110.
APA
Peifer, M., Fernández-Cuesta, L., Sos, M. L., George, J., Seidel, D., Kasper, L. H., Plenker, D., et al. (2012). Integrative genome analyses identify key somatic driver mutations of small-cell lung cancer. NATURE GENETICS, 44(10), 1104–1110.
Vancouver
1.
Peifer M, Fernández-Cuesta L, Sos ML, George J, Seidel D, Kasper LH, et al. Integrative genome analyses identify key somatic driver mutations of small-cell lung cancer. NATURE GENETICS. 2012;44(10):1104–10.
MLA
Peifer, Martin, Lynnette Fernández-Cuesta, Martin L Sos, et al. “Integrative Genome Analyses Identify Key Somatic Driver Mutations of Small-cell Lung Cancer.” NATURE GENETICS 44.10 (2012): 1104–1110. Print.
@article{3171598,
  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.},
  author       = {Peifer, Martin and Fern{\'a}ndez-Cuesta, Lynnette and Sos, Martin L and George, Julie and Seidel, Danila and Kasper, Lawryn H and Plenker, Dennis and Leenders, Frauke and Sun, Ruping and Zander, Thomas and Menon, Roopika and Koker, Mirjam and Dahmen, Ilona and M{\"u}ller, Christian and Di Cerbo, Vincenzo and Schildhaus, Hans-Ulrich and Altm{\"u}ller, Janine and Baessmann, Ingelore and Becker, Christian and De Wilde, Bram and Vandesompele, Jo and B{\"o}hm, Diana and Ans{\'e}n, Sascha and Gabler, Franziska and Wilkening, Ines and Heynck, Stefanie and Heuckmann, Johannes M and Lu, Xin and Carter, Scott L and Cibulskis, Kristian and Banerji, Shantanu and Getz, Gad and Park, Kwon-Sik and Rauh, Daniel and Gr{\"u}tter, Christian and Fischer, Matthias and Pasqualucci, Laura and Wright, Gavin and Wainer, Zoe and Russell, Prudence and Petersen, Iver and Chen, Yuan and Stoelben, Erich and Ludwig, Corinna and Schnabel, Philipp and Hoffmann, Hans and Muley, Thomas and Brockmann, Michael and Engel-Riedel, Walburga and Muscarella, Lucia A and Fazio, Vito M and Groen, Harry and Timens, Wim and Sietsma, Hannie and Thunnissen, Erik and Smit, Egbert and Heideman, Dani{\"e}lle AM and Snijders, Peter JF and Cappuzzo, Federico and Ligorio, Claudia and Damiani, Stefania and Field, John and Solberg, Steinar and Brustugun, Odd Terje and Lund-Iversen, Marius and S{\"a}nger, J{\"o}rg and Clement, Joachim H and Soltermann, Alex and Moch, Holger and Weder, Walter and Solomon, Benjamin and Soria, Jean-Charles and Validire, Pierre and Besse, Benjamin and Brambilla, Elisabeth and Brambilla, Christian and Lantuejoul, Sylvia and Lorimier, Philippe and Schneider, Peter M and Hallek, Michael and Pao, William and Meyerson, Matthew and Sage, Julien and Shendure, Jay and Schneider, Robert and B{\"u}ttner, Reinhard and Wolf, J{\"u}rgen and N{\"u}rnberg, Peter and Perner, Sven and Heukamp, Lukas C and Brindle, Paul K and Haas, Stefan and Thomas, Roman K},
  issn         = {1061-4036},
  journal      = {NATURE GENETICS},
  keyword      = {PROSTATE-CANCER,EGFR MUTATIONS,FREQUENT MUTATION,NEUROENDOCRINE TUMORS,ACUTE LYMPHOBLASTIC-LEUKEMIA,MOUSE MODEL,P53 REGULATION,EPH-RECEPTOR,E-CADHERIN,GENE},
  language     = {eng},
  number       = {10},
  pages        = {1104--1110},
  title        = {Integrative genome analyses identify key somatic driver mutations of small-cell lung cancer},
  url          = {http://dx.doi.org/10.1038/ng.2396},
  volume       = {44},
  year         = {2012},
}

Altmetric
View in Altmetric
Web of Science
Times cited: