George, Julie, Lim, Jing Shan, Jang, Se Jin, Cun, Yupeng ORCID: 0000-0002-4241-8099, Ozretic, Luka, Kong, Gu, Leenders, Frauke, Lu, Xin, Fernandez-Cuesta, Lynnette ORCID: 0000-0002-0724-6703, Bosco, Graziella, Mueller, Christian, Dahmen, Ilona, Jahchan, Nadine S., Park, Kwon-Sik, Yang, Dian, Karnezis, Anthony N., Vaka, Dedeepya ORCID: 0000-0001-7951-5514, Torres, Angela, Wang, Maia Segura, Korbel, Jan O., Menon, Roopika, Chun, Sung-Min ORCID: 0000-0002-3357-1382, Kim, Deokhoon, Wilkerson, Matt, Hayes, Neil, Engelmann, David, Puetzer, Brigitte, Bos, Marc, Michels, Sebastian, Vlasic, Ignacija, Seidel, Danila ORCID: 0000-0003-4388-3117, Pinther, Berit, Schaub, Philipp, Becker, Christian, Altmueller, Janine, Yokota, Jun, Kohno, Takashi, Iwakawa, Reika, Tsuta, Koji, Noguchi, Masayuki, Muley, Thomas, Hoffmann, Hans, Schnabel, Philipp A., Petersen, Iver, Chen, Yuan, Soltermann, Alex, Tischler, Verena ORCID: 0000-0002-6673-8329, Choi, Chang-min, Kim, Yong-Hee, Massion, Pierre P., Zou, Yong, Jovanovic, Dragana, Kontic, Milica, Wright, Gavin M., Russell, Prudence A., Solomon, Benjamin, Koch, Ina, Lindner, Michael, Muscarella, Lucia A., la Torre, Annamaria ORCID: 0000-0003-4199-1077, Field, John K. ORCID: 0000-0003-3951-6365, Jakopovic, Marko, Knezevic, Jelena, Castanos-Velez, Esmeralda ORCID: 0000-0002-2670-1118, Roz, Luca ORCID: 0000-0001-5817-7149, Pastorino, Ugo ORCID: 0000-0001-9974-7902, Brustugun, Odd-Terje, Lund-Iversen, Marius, Thunnissen, Erik, Koehler, Jens, Schuler, Martin, Botling, Johan, Sandelin, Martin ORCID: 0000-0002-0370-8819, Sanchez-Cespedes, Montserrat, Salvesen, Helga B., Achter, Viktor, Lang, Ulrich ORCID: 0000-0001-7166-0805, Bogus, Magdalena, Schneider, Peter M. ORCID: 0000-0003-0744-2349, Zander, Thomas, Ansen, Sascha, Hallek, Michael, Wolf, Juergen, Vingron, Martin, Yatabe, Yasushi ORCID: 0000-0003-1788-559X, Travis, William D., Nuernberg, Peter, Reinhardt, Christian, Perner, Sven, Heukamp, Lukas ORCID: 0000-0002-3388-3482, Buettner, Reinhard, Haas, Stefan A., Brambilla, Elisabeth, Peifer, Martin ORCID: 0000-0002-5243-5503, Sage, Julien and Thomas, Roman K. (2015). Comprehensive genomic profiles of small cell lung cancer. Nature, 524 (7563). S. 47 - 54. LONDON: NATURE PUBLISHING GROUP. ISSN 1476-4687

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Abstract

We 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.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
George, JulieUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lim, Jing ShanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Jang, Se JinUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Cun, YupengUNSPECIFIEDorcid.org/0000-0002-4241-8099UNSPECIFIED
Ozretic, LukaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kong, GuUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Leenders, FraukeUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lu, XinUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Fernandez-Cuesta, LynnetteUNSPECIFIEDorcid.org/0000-0002-0724-6703UNSPECIFIED
Bosco, GraziellaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Mueller, ChristianUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Dahmen, IlonaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Jahchan, Nadine S.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Park, Kwon-SikUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Yang, DianUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Karnezis, Anthony N.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Vaka, DedeepyaUNSPECIFIEDorcid.org/0000-0001-7951-5514UNSPECIFIED
Torres, AngelaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wang, Maia SeguraUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Korbel, Jan O.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Menon, RoopikaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Chun, Sung-MinUNSPECIFIEDorcid.org/0000-0002-3357-1382UNSPECIFIED
Kim, DeokhoonUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wilkerson, MattUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hayes, NeilUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Engelmann, DavidUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Puetzer, BrigitteUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bos, MarcUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Michels, SebastianUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Vlasic, IgnacijaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Seidel, DanilaUNSPECIFIEDorcid.org/0000-0003-4388-3117UNSPECIFIED
Pinther, BeritUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schaub, PhilippUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Becker, ChristianUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Altmueller, JanineUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Yokota, JunUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kohno, TakashiUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Iwakawa, ReikaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Tsuta, KojiUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Noguchi, MasayukiUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Muley, ThomasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hoffmann, HansUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schnabel, Philipp A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Petersen, IverUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Chen, YuanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Soltermann, AlexUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Tischler, VerenaUNSPECIFIEDorcid.org/0000-0002-6673-8329UNSPECIFIED
Choi, Chang-minUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kim, Yong-HeeUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Massion, Pierre P.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Zou, YongUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Jovanovic, DraganaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kontic, MilicaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wright, Gavin M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Russell, Prudence A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Solomon, BenjaminUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Koch, InaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lindner, MichaelUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Muscarella, Lucia A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
la Torre, AnnamariaUNSPECIFIEDorcid.org/0000-0003-4199-1077UNSPECIFIED
Field, John K.UNSPECIFIEDorcid.org/0000-0003-3951-6365UNSPECIFIED
Jakopovic, MarkoUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Knezevic, JelenaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Castanos-Velez, EsmeraldaUNSPECIFIEDorcid.org/0000-0002-2670-1118UNSPECIFIED
Roz, LucaUNSPECIFIEDorcid.org/0000-0001-5817-7149UNSPECIFIED
Pastorino, UgoUNSPECIFIEDorcid.org/0000-0001-9974-7902UNSPECIFIED
Brustugun, Odd-TerjeUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lund-Iversen, MariusUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Thunnissen, ErikUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Koehler, JensUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schuler, MartinUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Botling, JohanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Sandelin, MartinUNSPECIFIEDorcid.org/0000-0002-0370-8819UNSPECIFIED
Sanchez-Cespedes, MontserratUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Salvesen, Helga B.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Achter, ViktorUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lang, UlrichUNSPECIFIEDorcid.org/0000-0001-7166-0805UNSPECIFIED
Bogus, MagdalenaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schneider, Peter M.UNSPECIFIEDorcid.org/0000-0003-0744-2349UNSPECIFIED
Zander, ThomasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ansen, SaschaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hallek, MichaelUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wolf, JuergenUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Vingron, MartinUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Yatabe, YasushiUNSPECIFIEDorcid.org/0000-0003-1788-559XUNSPECIFIED
Travis, William D.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Nuernberg, PeterUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Reinhardt, ChristianUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Perner, SvenUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Heukamp, LukasUNSPECIFIEDorcid.org/0000-0002-3388-3482UNSPECIFIED
Buettner, ReinhardUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Haas, Stefan A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Brambilla, ElisabethUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Peifer, MartinUNSPECIFIEDorcid.org/0000-0002-5243-5503UNSPECIFIED
Sage, JulienUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Thomas, Roman K.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-396614
DOI: 10.1038/nature14664
Journal or Publication Title: Nature
Volume: 524
Number: 7563
Page Range: S. 47 - 54
Date: 2015
Publisher: NATURE PUBLISHING GROUP
Place of Publication: LONDON
ISSN: 1476-4687
Language: English
Faculty: Faculty of Mathematics and Natural Sciences
Divisions: Faculty of Mathematics and Natural Sciences > Department of Mathematics and Computer Science > Institute of Computer Science
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
CYCLE ARREST; C-KIT; NEUROENDOCRINE; MUTATIONS; NOTCH; CARCINOMA; PATHWAY; GROWTH; GENES; HETEROGENEITYMultiple languages
Multidisciplinary SciencesMultiple languages
Refereed: Yes
URI: http://kups.ub.uni-koeln.de/id/eprint/39661

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