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. Korbel; Roopika 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

doi:10.1038/nature14664

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

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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.

Original language	English
Pages (from-to)	47-53
Number of pages	7
Journal	Nature
Volume	524
Issue number	7563
DOIs	https://doi.org/10.1038/nature14664
State	Published - 6 Aug 2015
Externally published	Yes

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George, J., Lim, J. S., Jang, S. J., Cun, Y., Ozretia, L., Kong, G., Leenders, F., Lu, X., Fernández-Cuesta, L., Bosco, G., Müller, C., Dahmen, I., Jahchan, N. S., Park, K. S., Yang, D., Karnezis, A. N., Vaka, D., Torres, A., Wang, M. S., ... Thomas, R. K. (2015). Comprehensive genomic profiles of small cell lung cancer. Nature, 524(7563), 47-53. https://doi.org/10.1038/nature14664

@article{2e5bda67d8b9487b8b7f5bfb61d4ef4d,

title = "Comprehensive genomic profiles of small cell lung cancer",

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.",

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

year = "2015",

month = aug,

day = "6",

doi = "10.1038/nature14664",

language = "English",

volume = "524",

pages = "47--53",

journal = "Nature",

issn = "0028-0836",

number = "7563",

}

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

TY - JOUR

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.

UR - http://www.scopus.com/inward/record.url?scp=84938132350&partnerID=8YFLogxK

U2 - 10.1038/nature14664

DO - 10.1038/nature14664

M3 - Article

C2 - 26168399

AN - SCOPUS:84938132350

SN - 0028-0836

VL - 524

SP - 47

EP - 53

JO - Nature

JF - Nature

IS - 7563

ER -

Comprehensive genomic profiles of small cell lung cancer

Abstract

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