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  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., et al. (2012). Integrative genome analyses identify key somatic driver mutations of small-cell lung cancer. Nature Genetics, 44(10), 1104-1110. doi:10.1038/ng.2396.

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Item Permalink: http://hdl.handle.net/11858/00-001M-0000-000E-E872-0 Version Permalink: http://hdl.handle.net/11858/00-001M-0000-000E-E873-E
Genre: Journal Article

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Peifer, M., Author
Fernandez-Cuesta, L., Author
Sos, M. L., Author
George, J., Author
Seidel, D., Author
Kasper, L. H., Author
Plenker, D., Author
Leenders, F., Author
Sun, R., Author
Zander, T., Author
Menon, R., Author
Koker, M., Author
Dahmen, I., Author
Muller, C., Author
Di Cerbo, V., Author
Schildhaus, H. U., Author
Altmuller, J., Author
Baessmann, I., Author
Becker, C., Author
de Wilde, B., Author
Vandesompele, J., AuthorBohm, D., AuthorAnsen, S., AuthorGabler, F., AuthorWilkening, I., AuthorHeynck, S., AuthorHeuckmann, J. M., AuthorLu, X., AuthorCarter, S. L., AuthorCibulskis, K., AuthorBanerji, S., AuthorGetz, G., AuthorPark, K. S., AuthorRauh, D., AuthorGrutter, C., AuthorFischer, M., AuthorPasqualucci, L., AuthorWright, G., AuthorWainer, Z., AuthorRussell, P., AuthorPetersen, I., AuthorChen, Y., AuthorStoelben, E., AuthorLudwig, C., AuthorSchnabel, P., AuthorHoffmann, H., AuthorMuley, T., AuthorBrockmann, M., AuthorEngel-Riedel, W., AuthorMuscarella, L. A., AuthorFazio, V. M., AuthorGroen, H., AuthorTimens, W., AuthorSietsma, H., AuthorThunnissen, E., AuthorSmit, E., AuthorHeideman, D. A., AuthorSnijders, P. J., AuthorCappuzzo, F., AuthorLigorio, C., AuthorDamiani, S., AuthorField, J., AuthorSolberg, S., AuthorBrustugun, O. T., AuthorLund-Iversen, M., AuthorSanger, J., AuthorClement, J. H., AuthorSoltermann, A., AuthorMoch, H., AuthorWeder, W., AuthorSolomon, B., AuthorSoria, J. C., AuthorValidire, P., AuthorBesse, B., AuthorBrambilla, E., AuthorBrambilla, C., AuthorLantuejoul, S., AuthorLorimier, P., AuthorSchneider, P. M., AuthorHallek, M., AuthorPao, W., AuthorMeyerson, M., AuthorSage, J., AuthorShendure, J., AuthorSchneider, R., AuthorButtner, R., AuthorWolf, J., AuthorNurnberg, P., AuthorPerner, S., AuthorHeukamp, L. C., AuthorBrindle, P. K., AuthorHaas, S.1, Author              Thomas, R. K., Author more..
Affiliations:
1Gene Structure and Array Design (Stefan Haas), Dept. of Computational Molecular Biology (Head: Martin Vingron), Max Planck Institute for Molecular Genetics, Max Planck Society, Berlin, Germany, ou_1479640              

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Free keywords: Amino Acid Substitution Animals CREB-Binding Protein/genetics Cell Line, Tumor DNA Copy Number Variations DNA Mutational Analysis E1A-Associated p300 Protein/genetics Gene Expression Profiling Gene Regulatory Networks *Genome, Human Genome-Wide Association Study Humans Intercellular Signaling Peptides and Proteins/genetics Lung Neoplasms/*genetics Mice Mice, Knockout Models, Molecular Mutation Myeloid-Lymphoid Leukemia Protein/genetics Nerve Tissue Proteins/genetics Oligonucleotide Array Sequence Analysis PTEN Phosphohydrolase/genetics Polymorphism, Single Nucleotide Protein Processing, Post-Translational/genetics Retinoblastoma Protein/genetics Small Cell Lung Carcinoma/*genetics Tumor Suppressor Protein p53/genetics
 Abstract: 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.

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Language(s): eng - English
 Dates: 2012-09-022012-10
 Publication Status: Published in print
 Pages: -
 Publishing info: -
 Table of Contents: -
 Rev. Type: Peer
 Identifiers: DOI: 10.1038/ng.2396
 Degree: -

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Title: Nature Genetics
  Other : Nature Genet.
Source Genre: Journal
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Publ. Info: New York, NY : Nature America, Inc.
Pages: - Volume / Issue: 44 (10) Sequence Number: - Start / End Page: 1104 - 1110 Identifier: ISSN: 1061-4036
CoNE: https://pure.mpg.de/cone/journals/resource/954925598609