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

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Item Type:	Article
Title:	Integrative genome analyses identify key somatic driver mutations of small-cell lung cancer
Creators Name:	Peifer, M., Fernández-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., Müller, C., Di Cerbo, V., Schildhaus, H.U., Altmüller, J., Baessmann, I., Becker, C., de Wilde, B., Vandesompele, J., Böhm, D., Ansén, 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., Grütter, 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., Sänger, 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., Büttner, R., Wolf, J., Nürnberg, P., Perner, S., Heukamp, L.C., Brindle, P.K., Haas, S. and Thomas, R.K.
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.
Keywords:	Epigenetics, Mutation, Small-Cell Lung Cancer, Animals, Mice
Source:	Nature Genetics
ISSN:	1061-4036
Publisher:	Nature Publishing Group
Volume:	44
Number:	10
Page Range:	1104-10
Date:	October 2012
Official Publication:	https://doi.org/10.1038/ng.2396
PubMed:	View item in PubMed

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