Comprehensive genomic profiles of small cell lung cancer

Julie George, Jing Shan Lim, Se Jin Jang, Yupeng Cun, Luka Ozretia, Gu Kong, Frauke Leenders, Xin Lu, Lynnette Fernández-Cuesta, Graziella Bosco, Christian Müller, Ilona Dahmen, Nadine S. Jahchan, Kwon Sik Park, Dian Yang, Anthony N. Karnezis, Dedeepya Vaka, Angela Torres, Maia Segura Wang, Jan O. KorbelRoopika Menon, Sung Min Chun, Deokhoon Kim, Matt Wilkerson, Neil Hayes, David Engelmann, Brigitte Pützer, Marc Bos, Sebastian Michels, Ignacija Vlasic, Danila Seidel, Berit Pinther, Philipp Schaub, Christian Becker, Janine Altmüller, Jun Yokota, Takashi Kohno, Reika Iwakawa, Koji Tsuta, Masayuki Noguchi, Thomas Muley, Hans Hoffmann, Philipp A. Schnabel, Iver Petersen, Yuan Chen, Alex Soltermann, Verena Tischler, Chang Min Choi, Yong Hee Kim, Pierre P. Massion, Yong Zou, Dragana Jovanovic, Milica Kontic, Gavin M. Wright, Prudence A. Russell, Benjamin Solomon, Ina Koch, Michael Lindner, Lucia A. Muscarella, Annamaria La Torre, John K. Field, Marko Jakopovic, Jelena Knezevic, Esmeralda Castaños-Vélez, Luca Roz, Ugo Pastorino, Odd Terje Brustugun, Marius Lund-Iversen, Erik Thunnissen, Jens Köhler, Martin Schuler, Johan Botling, Martin Sandelin, Montserrat Sanchez-Cespedes, Helga B. Salvesen, Viktor Achter, Ulrich Lang, Magdalena Bogus, Peter M. Schneider, Thomas Zander, Sascha Ansén, Michael Hallek, Jürgen Wolf, Martin Vingron, Yasushi Yatabe, William D. Travis, Peter Nürnberg, Christian Reinhardt, Sven Perner, Lukas Heukamp, Reinhard Büttner, Stefan A. Haas, Elisabeth Brambilla, Martin Peifer, Julien Sage, Roman K. Thomas

Research output: Contribution to journalArticle

554 Citations (Scopus)

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, TP73I "ex2/3. 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.

Original languageEnglish
Pages (from-to)47-53
Number of pages7
JournalNature
Volume524
Issue number7563
DOIs
Publication statusPublished - Aug 6 2015

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Small Cell Lung Carcinoma
Neoplasms
Genes
Genome
Biological Phenomena
Mutation
Cyclin D1
Phosphotransferases
Gene Expression
Therapeutics

ASJC Scopus subject areas

  • General

Cite this

George, J., Lim, J. S., Jang, S. J., Cun, Y., Ozretia, L., Kong, G., ... Thomas, R. K. (2015). Comprehensive genomic profiles of small cell lung cancer. Nature, 524(7563), 47-53. https://doi.org/10.1038/nature14664

Comprehensive genomic profiles of small cell lung cancer. / George, Julie; Lim, Jing Shan; Jang, Se Jin; Cun, Yupeng; Ozretia, Luka; Kong, Gu; Leenders, Frauke; Lu, Xin; Fernández-Cuesta, Lynnette; Bosco, Graziella; Müller, Christian; Dahmen, Ilona; Jahchan, Nadine S.; Park, Kwon Sik; Yang, Dian; Karnezis, Anthony N.; Vaka, Dedeepya; Torres, Angela; Wang, Maia Segura; Korbel, Jan O.; Menon, Roopika; Chun, Sung Min; Kim, Deokhoon; Wilkerson, Matt; Hayes, Neil; Engelmann, David; Pützer, Brigitte; Bos, Marc; Michels, Sebastian; Vlasic, Ignacija; Seidel, Danila; Pinther, Berit; Schaub, Philipp; Becker, Christian; Altmüller, 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; 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; Field, John K.; Jakopovic, Marko; Knezevic, Jelena; Castaños-Vélez, Esmeralda; Roz, Luca; Pastorino, Ugo; Brustugun, Odd Terje; Lund-Iversen, Marius; Thunnissen, Erik; Köhler, Jens; Schuler, Martin; Botling, Johan; Sandelin, Martin; Sanchez-Cespedes, Montserrat; Salvesen, Helga B.; Achter, Viktor; Lang, Ulrich; Bogus, Magdalena; Schneider, Peter M.; Zander, Thomas; Ansén, Sascha; Hallek, Michael; Wolf, Jürgen; Vingron, Martin; Yatabe, Yasushi; Travis, William D.; Nürnberg, Peter; Reinhardt, Christian; Perner, Sven; Heukamp, Lukas; Büttner, Reinhard; Haas, Stefan A.; Brambilla, Elisabeth; Peifer, Martin; Sage, Julien; Thomas, Roman K.

In: Nature, Vol. 524, No. 7563, 06.08.2015, p. 47-53.

Research output: Contribution to journalArticle

George, J, Lim, JS, Jang, SJ, Cun, Y, Ozretia, L, Kong, G, Leenders, F, Lu, X, Fernández-Cuesta, L, Bosco, G, Müller, C, Dahmen, I, Jahchan, NS, Park, KS, Yang, D, Karnezis, AN, Vaka, D, Torres, A, Wang, MS, Korbel, JO, Menon, R, Chun, SM, Kim, D, Wilkerson, M, Hayes, N, Engelmann, D, Pützer, B, Bos, M, Michels, S, Vlasic, I, Seidel, D, Pinther, B, Schaub, P, Becker, C, Altmüller, J, Yokota, J, Kohno, T, Iwakawa, R, Tsuta, K, Noguchi, M, Muley, T, Hoffmann, H, Schnabel, PA, Petersen, I, Chen, Y, Soltermann, A, Tischler, V, Choi, CM, Kim, YH, Massion, PP, Zou, Y, Jovanovic, D, Kontic, M, Wright, GM, Russell, PA, Solomon, B, Koch, I, Lindner, M, Muscarella, LA, La Torre, A, Field, JK, Jakopovic, M, Knezevic, J, Castaños-Vélez, E, Roz, L, Pastorino, U, Brustugun, OT, Lund-Iversen, M, Thunnissen, E, Köhler, J, Schuler, M, Botling, J, Sandelin, M, Sanchez-Cespedes, M, Salvesen, HB, Achter, V, Lang, U, Bogus, M, Schneider, PM, Zander, T, Ansén, S, Hallek, M, Wolf, J, Vingron, M, Yatabe, Y, Travis, WD, Nürnberg, P, Reinhardt, C, Perner, S, Heukamp, L, Büttner, R, Haas, SA, Brambilla, E, Peifer, M, Sage, J & Thomas, RK 2015, 'Comprehensive genomic profiles of small cell lung cancer', Nature, vol. 524, no. 7563, pp. 47-53. https://doi.org/10.1038/nature14664
George J, Lim JS, Jang SJ, Cun Y, Ozretia L, Kong G et al. Comprehensive genomic profiles of small cell lung cancer. Nature. 2015 Aug 6;524(7563):47-53. https://doi.org/10.1038/nature14664
George, Julie ; Lim, Jing Shan ; Jang, Se Jin ; Cun, Yupeng ; Ozretia, Luka ; Kong, Gu ; Leenders, Frauke ; Lu, Xin ; Fernández-Cuesta, Lynnette ; Bosco, Graziella ; Müller, Christian ; Dahmen, Ilona ; Jahchan, Nadine S. ; Park, Kwon Sik ; Yang, Dian ; Karnezis, Anthony N. ; Vaka, Dedeepya ; Torres, Angela ; Wang, Maia Segura ; Korbel, Jan O. ; Menon, Roopika ; Chun, Sung Min ; Kim, Deokhoon ; Wilkerson, Matt ; Hayes, Neil ; Engelmann, David ; Pützer, Brigitte ; Bos, Marc ; Michels, Sebastian ; Vlasic, Ignacija ; Seidel, Danila ; Pinther, Berit ; Schaub, Philipp ; Becker, Christian ; Altmüller, 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 ; 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 ; Field, John K. ; Jakopovic, Marko ; Knezevic, Jelena ; Castaños-Vélez, Esmeralda ; Roz, Luca ; Pastorino, Ugo ; Brustugun, Odd Terje ; Lund-Iversen, Marius ; Thunnissen, Erik ; Köhler, Jens ; Schuler, Martin ; Botling, Johan ; Sandelin, Martin ; Sanchez-Cespedes, Montserrat ; Salvesen, Helga B. ; Achter, Viktor ; Lang, Ulrich ; Bogus, Magdalena ; Schneider, Peter M. ; Zander, Thomas ; Ansén, Sascha ; Hallek, Michael ; Wolf, Jürgen ; Vingron, Martin ; Yatabe, Yasushi ; Travis, William D. ; Nürnberg, Peter ; Reinhardt, Christian ; Perner, Sven ; Heukamp, Lukas ; Büttner, Reinhard ; Haas, Stefan A. ; Brambilla, Elisabeth ; Peifer, Martin ; Sage, Julien ; Thomas, Roman K. / Comprehensive genomic profiles of small cell lung cancer. In: Nature. 2015 ; Vol. 524, No. 7563. pp. 47-53.
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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, TP73I {"}ex2/3. 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.",
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T1 - Comprehensive genomic profiles of small cell lung cancer

AU - George, Julie

AU - Lim, Jing Shan

AU - Jang, Se Jin

AU - Cun, Yupeng

AU - Ozretia, Luka

AU - Kong, Gu

AU - Leenders, Frauke

AU - Lu, Xin

AU - Fernández-Cuesta, Lynnette

AU - Bosco, Graziella

AU - Müller, Christian

AU - Dahmen, Ilona

AU - Jahchan, Nadine S.

AU - Park, Kwon Sik

AU - Yang, Dian

AU - Karnezis, Anthony N.

AU - Vaka, Dedeepya

AU - Torres, Angela

AU - Wang, Maia Segura

AU - Korbel, Jan O.

AU - Menon, Roopika

AU - Chun, Sung Min

AU - Kim, Deokhoon

AU - Wilkerson, Matt

AU - Hayes, Neil

AU - Engelmann, David

AU - Pützer, Brigitte

AU - Bos, Marc

AU - Michels, Sebastian

AU - Vlasic, Ignacija

AU - Seidel, Danila

AU - Pinther, Berit

AU - Schaub, Philipp

AU - Becker, Christian

AU - Altmüller, Janine

AU - Yokota, Jun

AU - Kohno, Takashi

AU - Iwakawa, Reika

AU - Tsuta, Koji

AU - Noguchi, Masayuki

AU - Muley, Thomas

AU - Hoffmann, Hans

AU - Schnabel, Philipp A.

AU - Petersen, Iver

AU - Chen, Yuan

AU - Soltermann, Alex

AU - Tischler, Verena

AU - Choi, Chang Min

AU - Kim, Yong Hee

AU - Massion, Pierre P.

AU - Zou, Yong

AU - Jovanovic, Dragana

AU - Kontic, Milica

AU - Wright, Gavin M.

AU - Russell, Prudence A.

AU - Solomon, Benjamin

AU - Koch, Ina

AU - Lindner, Michael

AU - Muscarella, Lucia A.

AU - La Torre, Annamaria

AU - Field, John K.

AU - Jakopovic, Marko

AU - Knezevic, Jelena

AU - Castaños-Vélez, Esmeralda

AU - Roz, Luca

AU - Pastorino, Ugo

AU - Brustugun, Odd Terje

AU - Lund-Iversen, Marius

AU - Thunnissen, Erik

AU - Köhler, Jens

AU - Schuler, Martin

AU - Botling, Johan

AU - Sandelin, Martin

AU - Sanchez-Cespedes, Montserrat

AU - Salvesen, Helga B.

AU - Achter, Viktor

AU - Lang, Ulrich

AU - Bogus, Magdalena

AU - Schneider, Peter M.

AU - Zander, Thomas

AU - Ansén, Sascha

AU - Hallek, Michael

AU - Wolf, Jürgen

AU - Vingron, Martin

AU - Yatabe, Yasushi

AU - Travis, William D.

AU - Nürnberg, Peter

AU - Reinhardt, Christian

AU - Perner, Sven

AU - Heukamp, Lukas

AU - Büttner, Reinhard

AU - Haas, Stefan A.

AU - Brambilla, Elisabeth

AU - Peifer, Martin

AU - Sage, Julien

AU - Thomas, Roman K.

PY - 2015/8/6

Y1 - 2015/8/6

N2 - 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, TP73I "ex2/3. 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.

AB - 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, TP73I "ex2/3. 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.

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