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

Abstract

Small-cell lung cancer (SCLC) is an aggressive lung tumor subtype with poor prognosis1,2,3. 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 mice4. 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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Figure 1: Identification of SCNAs, chimeric transcripts and genomic rearrangements in human and mouse SCLC tumors.
Figure 2: Comparison of resected and autopsy samples and identification of candidate driver mutations.
Figure 3: Recurrent mutations affecting SLIT2, CREBBP and EP300.
Figure 4: Functional analysis of CREBBP and EP300.
Figure 5: Mutation spectra of TP53 and RB1 and genetic pathways altered in SCLC.

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Acknowledgements

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).

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M.P., L.F.-C., M.L.S., J.G., D.S., L.H.K., F.L.,T.Z., R.M., J.V., P.S., J. Sage, R. Schneider, R.B., S.P., L.C.H., P.K.B. and R.K.T. conceived and designed the experiments. L.F.-C., M.L.S., J.G., D.S., L.H.K., D.P., R.M., M.K., I.D., C.M., V.D.C., H.-U.S., J.A., I.B., C. Becker, B.d.W., D.B., F.G., I.W., S. Heynck, J.M.H. and P.M.S. performed experiments. M.P., L.F.-C., M.L.S., J.G., D.S., L.H.K., D.P., F.L., R. Sun, T.Z., R.M., V.D.C., B.d.W., J.V., X.L., W.P., M.M., J. Sage, R. Schneider, S.P., L.C.H., P.K.B., S. Haas and R.K.T. analyzed the data. M.P., R. Sun, S.A., S.L.C., K.C., S.B., G.G., K.-S.P., D.R., C.G., M.F., L.P., G.W., Z.W., P.R., I.P., Y.C., E. Stoelben, C. Ludwig, P.S., H.H., T.M., M.B., W.E.-R., L.A.M., V.M.F., H.G., W.T., H.S., E.T., E. Smit, D.A.M.H., P.J.F.S., F.C., C. Ligorio, S.D., J.F., S.S., O.T.B., M.L.-I., J. Sänger, J.H.C., A.S., H.M., W.W., B.S., J.-C.S., P.V., B.B., E.B., C. Brambilla, S.L., P.L., M.H., J. Sage, J. Shendure, R. Schneider, R.B., S.P., L.C.H., J.W., P.N., L.C.H., P.K.B. and S. Haas contributed reagents, materials or analysis tools. M.P., L.F.-C. and R.K.T. wrote the manuscript.

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Correspondence to Roman K Thomas.

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R.K.T. reports the following potential sources of conflict of interest: consulting and lecture fees (Sanofi-Aventis, Merck, Bayer, Eli Lilly, Roche, Boehringer Ingelheim, Johnson & Johnson, AstraZeneca, Atlas-Biolabs and Daiichi-Sankyo) and research support (AstraZeneca, Merck and EOS). R.K.T. is a founder and shareholder of Blackfield, a company involved in cancer genome analysis services and cancer genomics–based drug discovery. M.P. and J.M.H. are shareholders of Blackfield. J.M.H. is a full-time employee of Blackfield.

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Peifer, M., Fernández-Cuesta, L., Sos, M. et al. Integrative genome analyses identify key somatic driver mutations of small-cell lung cancer. Nat Genet 44, 1104–1110 (2012). https://doi.org/10.1038/ng.2396

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