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dc.identifier.citationNATURE, v. 524, NO 7563, Page. 47-73en_US
dc.description.abstractWe have sequenced the genomes of 110 small cell lung cancers (SCLC), one of the deadliest human cancers. In nearly all the tumours analysed we found bi-allelic inactivation of TP53 and RB1, sometimes by complex genomic rearrangements. Two tumours with wild-type RB1 had evidence of chromothripsis leading to overexpression of cyclin D1 (encoded by the CCND1 gene), revealing an alternative mechanism of Rb1 deregulation. Thus, loss of the tumour suppressors TP53 and RB1 is obligatory in SCLC. We discovered somatic genomic rearrangements of TP73 that create an oncogenic version of this gene, TP73Dex2/3. In rare cases, SCLC tumours exhibited kinase gene mutations, providing a possible therapeutic opportunity for individual patients. Finally, we observed inactivating mutations in NOTCH family genes in 25% of human SCLC. Accordingly, activation of Notch signalling in a pre-clinical SCLC mouse model strikingly reduced the number of tumours and extended the survival of the mutant mice. Furthermore, neuroendocrine gene expression was abrogated by Notch activity in SCLC cells. This first comprehensive study of somatic genome alterations in SCLC uncovers several key biological processes and identifies candidate therapeutic targets in this highly lethal form of cancer.en_US
dc.description.sponsorshipWe are grateful to all the patients who contributed their tumour specimens. We thank the computing center of the University of Cologne (RRZK) for providing the CPU time on the DFG-funded supercomputer ‘CHEOPS’, as well as for the support. We thank S. Artavanis-Tsakonas and S. Fre for the gift of the mice with inducible NICD expression. We thank C. Nguyen, J. Berg, J. Heuckmann, F. Malchers, C. Lovely and A. Bernschein for scientific discussions and advice. We thank Genentech/gRED for providing raw sequencing data from a previously published study3. Some tumors in these studies were provided by the LungBiobank Heidelberg, member of the NCT-Tissue bank, the biomaterial bank Heidelberg and the biobank platform of the German Center for Lung Research, Heidelberg, Germany. This work was supported by the German Cancer Aid (Deutsche Krebshilfe) as part of the small cell lung cancer genome sequencing consortium (grant ID: 109679 to R.K.T., M.P., R.B., P.N., M.V. and S.A.H.). Further support was provided by the Korea Research Foundation (KRF 2011-0030105; grant to S.J.J.). Additional funding was provided by the NIH (5R01CA114102-08 to J.S.), the German Ministry of Science and Education (BMBF) as part of the NGFNplus program (grant 01GS08101 to R.K.T., J.W. and P.N.) and as part of the e:Med program (grant no. 01ZX1303A to R.K.T., J.W., C.R., R.B. and M.P. and grant no. 01ZX1406 to M.P.), by the Deutsche Forschungsgemeinschaft (DFG; through TH1386/3-1 to R.K.T and KFO-286 to P.N.), by the German federal state North Rhine Westphalia (NRW), by the European Union (European Regional Development Fund: Investing In Your Future) as part of the PerMed NRW initiative (grant 005-1111-0025 to R.K.T., J.W. and R.B.), by SFB832 (TP6 to R.K.T., TP5 to L.C.H.), by the Deutsche Krebshilfe as part of the Oncology Centers of Excellence funding program (to R.B., R.K.T. and M.S.), by the EU-Framework program CURELUNG (HEALTH-F2-2010-258677 to R.K.T., J.W., J.K.F., L.R., M.S.C. and E.B.), by Stand Up To Cancer — American Association of Cancer Research Innovative Research Grant (SU2C-AACR-IR60109 to R.K.T.), by the German Consortium for Translational Cancer Research (DKTK) Joint Funding program, by the National Cancer Center Research and Development Fund (NCC Biobank: 23A-1, to T.K., J.Y. and R.I.), by the Italian Ministry of Health (Ricerca Corrente RC1303LO57 and GR program 2010-2316264 to L.A.M.), by the Roy Castle Lung Cancer Foundation UK (to J.K.F.), by the AIRC/MGAF grant 12983 (to L.A.M.) and by A*STAR in Singapore (scholarship to J.S.L.). J.S. is the Harriet and Mary Zelencik Scientist in Children’s Cancer and Blood Diseases.en_US
dc.subjectCancer genomicsen_US
dc.titleComprehensive genomic profiles of small cell lung canceren_US
dc.contributor.googleauthorGeorge, Julie-
dc.contributor.googleauthorLim, JIng Shan-
dc.contributor.googleauthorJang, Se Jin-
dc.contributor.googleauthorCun, Yupeng-
dc.contributor.googleauthorOzretić, Luka-
dc.contributor.googleauthorKong, Gu-
dc.contributor.googleauthorLeenders, Frauke-
dc.contributor.googleauthorLu, Xin-
dc.contributor.googleauthorFernández-Cuesta, Lynnette-
dc.contributor.googleauthorBosco, Graziella-
dc.sector.daehakCOLLEGE OF MEDICINE[S]-
dc.sector.departmentDEPARTMENT OF MEDICINE-
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