Comprehensive genomic profiles of small cell lung cancer
Authorized Users Only
2015
Authors
George, JulieLim, Jing Shan
Jang, Se Jin
Cun, Yupeng
Ozretic, Luka
Kong, Gu
Leenders, Frauke
Lu, Xin
Fernandez-Cuesta, Lynnette
Bosco, Graziella
Mueller, 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
Puetzer, Brigitte
Bos, Marc
Michels, Sebastian
Vlasic, Ignacija
Seidel, Danila
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
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
Knežević, Jelena
Castanos-Velez, Esmeralda
Roz, Luca
Pastorino, Ugo
Brustugun, Odd-Terje
Lund-Iversen, Marius
Thunnissen, Erik
Koehler, Jens
Schuler, Martin
Botling, Johan
Sandelin, Martin
Sanchez-Cespedes, Montserrat
Salvesen, Helga B.
Achter, Viktor
Lang, Ulrich
Bogus, Magdalena
Schneider, Peter M.
Zander, Thomas
Ansen, Sascha
Hallek, Michael
Wolf, Juergen
Vingron, Martin
Yatabe, Yasushi
Travis, William D.
Nuernberg, Peter
Reinhardt, Christian
Perner, Sven
Heukamp, Lukas
Buettner, Reinhard
Haas, Stefan A.
Brambilla, Elisabeth
Peifer, Martin
Sage, Julien
Thomas, Roman K.
Article (Published version)
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Show full item recordAbstract
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. Furthermo...re, 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.
Source:
Nature, 2015, 524, 7563, 47-53Funding / projects:
- CURELUNG - Determining (epi)genetic therapeutic signatures for improving lung cancer prognosis (EU-FP7-258677)
- DFG, German Cancer Aid (Deutsche Krebshilfe) as part of the small cell lung cancer genome sequencing consortium [109679]
- Korea Research Foundation [KRF 2011-0030105]
- NIH [5R01CA114102-08]
- German Ministry of Science and Education (BMBF) [01GS08101, 01ZX1303A, 01ZX1406]
- Deutsche Forschungsgemeinschaft (DFG) [TH1386/3-1, KFO-286]
- German federal state North Rhine Westphalia (NRW), European Union as part of the PerMed NRW initiative [005-1111-0025]
- Deutsche Krebshilfe as part of the Oncology Centers of Excellence, Stand Up To Cancer-American Association of Cancer Research Innovative Research Grant [SU2C-AACR-IR60109]
- German Consortium for Translational Cancer Research (DKTK), National Cancer Center Research and Development Fund [NCC Biobank: 23A-1]
- Italian Ministry of Health [RC1303LO57, 2010-2316264]
- Roy Castle Lung Cancer Foundation UK, AIRC/MGAF [12983]
- A*STAR in Singapore
DOI: 10.1038/nature14664
ISSN: 0028-0836; 1476-4687
PubMed: 26168399
WoS: 000359002300029
Scopus: 2-s2.0-84938132350
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VinčaTY - JOUR AU - George, Julie AU - Lim, Jing Shan AU - Jang, Se Jin AU - Cun, Yupeng AU - Ozretic, Luka AU - Kong, Gu AU - Leenders, Frauke AU - Lu, Xin AU - Fernandez-Cuesta, Lynnette AU - Bosco, Graziella AU - Mueller, 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 - Puetzer, Brigitte AU - Bos, Marc AU - Michels, Sebastian AU - Vlasic, Ignacija AU - Seidel, Danila AU - Pinther, Berit AU - Schaub, Philipp AU - Becker, Christian AU - Altmueller, 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 - Knežević, Jelena AU - Castanos-Velez, Esmeralda AU - Roz, Luca AU - Pastorino, Ugo AU - Brustugun, Odd-Terje AU - Lund-Iversen, Marius AU - Thunnissen, Erik AU - Koehler, 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 - Ansen, Sascha AU - Hallek, Michael AU - Wolf, Juergen AU - Vingron, Martin AU - Yatabe, Yasushi AU - Travis, William D. AU - Nuernberg, Peter AU - Reinhardt, Christian AU - Perner, Sven AU - Heukamp, Lukas AU - Buettner, Reinhard AU - Haas, Stefan A. AU - Brambilla, Elisabeth AU - Peifer, Martin AU - Sage, Julien AU - Thomas, Roman K. PY - 2015 UR - https://vinar.vin.bg.ac.rs/handle/123456789/685 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, 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. T2 - Nature T1 - Comprehensive genomic profiles of small cell lung cancer VL - 524 IS - 7563 SP - 47 EP - 53 DO - 10.1038/nature14664 ER -
@article{ author = "George, Julie and Lim, Jing Shan and Jang, Se Jin and Cun, Yupeng and Ozretic, Luka and Kong, Gu and Leenders, Frauke and Lu, Xin and Fernandez-Cuesta, Lynnette and Bosco, Graziella and Mueller, Christian and Dahmen, Ilona and Jahchan, Nadine S. and Park, Kwon-Sik and Yang, Dian and Karnezis, Anthony N. and Vaka, Dedeepya and Torres, Angela and Wang, Maia Segura and Korbel, Jan O. and Menon, Roopika and Chun, Sung-Min and Kim, Deokhoon and Wilkerson, Matt and Hayes, Neil and Engelmann, David and Puetzer, Brigitte and Bos, Marc and Michels, Sebastian and Vlasic, Ignacija and Seidel, Danila and Pinther, Berit and Schaub, Philipp and Becker, Christian and Altmueller, Janine and Yokota, Jun and Kohno, Takashi and Iwakawa, Reika and Tsuta, Koji and Noguchi, Masayuki and Muley, Thomas and Hoffmann, Hans and Schnabel, Philipp A. and Petersen, Iver and Chen, Yuan and Soltermann, Alex and Tischler, Verena and Choi, Chang-min and Kim, Yong-Hee and Massion, Pierre P. and Zou, Yong and Jovanovic, Dragana and Kontic, Milica and Wright, Gavin M. and Russell, Prudence A. and Solomon, Benjamin and Koch, Ina and Lindner, Michael and Muscarella, Lucia A. and la Torre, Annamaria and Field, John K. and Jakopovic, Marko and Knežević, Jelena and Castanos-Velez, Esmeralda and Roz, Luca and Pastorino, Ugo and Brustugun, Odd-Terje and Lund-Iversen, Marius and Thunnissen, Erik and Koehler, Jens and Schuler, Martin and Botling, Johan and Sandelin, Martin and Sanchez-Cespedes, Montserrat and Salvesen, Helga B. and Achter, Viktor and Lang, Ulrich and Bogus, Magdalena and Schneider, Peter M. and Zander, Thomas and Ansen, Sascha and Hallek, Michael and Wolf, Juergen and Vingron, Martin and Yatabe, Yasushi and Travis, William D. and Nuernberg, Peter and Reinhardt, Christian and Perner, Sven and Heukamp, Lukas and Buettner, Reinhard and Haas, Stefan A. and Brambilla, Elisabeth and Peifer, Martin and Sage, Julien and Thomas, Roman K.", year = "2015", 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.", journal = "Nature", title = "Comprehensive genomic profiles of small cell lung cancer", volume = "524", number = "7563", pages = "47-53", doi = "10.1038/nature14664" }
George, J., Lim, J. S., Jang, S. J., Cun, Y., Ozretic, L., Kong, G., Leenders, F., Lu, X., Fernandez-Cuesta, L., Bosco, G., Mueller, C., Dahmen, I., Jahchan, N. S., Park, K., Yang, D., Karnezis, A. N., Vaka, D., Torres, A., Wang, M. S., Korbel, J. O., Menon, R., Chun, S., Kim, D., Wilkerson, M., Hayes, N., Engelmann, D., Puetzer, B., Bos, M., Michels, S., Vlasic, I., Seidel, D., Pinther, B., Schaub, P., Becker, C., Altmueller, J., Yokota, J., Kohno, T., Iwakawa, R., Tsuta, K., Noguchi, M., Muley, T., Hoffmann, H., Schnabel, P. A., Petersen, I., Chen, Y., Soltermann, A., Tischler, V., Choi, C., Kim, Y., Massion, P. P., Zou, Y., Jovanovic, D., Kontic, M., Wright, G. M., Russell, P. A., Solomon, B., Koch, I., Lindner, M., Muscarella, L. A., la Torre, A., Field, J. K., Jakopovic, M., Knežević, J., Castanos-Velez, E., Roz, L., Pastorino, U., Brustugun, O., Lund-Iversen, M., Thunnissen, E., Koehler, J., Schuler, M., Botling, J., Sandelin, M., Sanchez-Cespedes, M., Salvesen, H. B., Achter, V., Lang, U., Bogus, M., Schneider, P. M., Zander, T., Ansen, S., Hallek, M., Wolf, J., Vingron, M., Yatabe, Y., Travis, W. D., Nuernberg, P., Reinhardt, C., Perner, S., Heukamp, L., Buettner, R., Haas, S. A., Brambilla, E., Peifer, M., Sage, J.,& Thomas, R. K.. (2015). Comprehensive genomic profiles of small cell lung cancer. in Nature, 524(7563), 47-53. https://doi.org/10.1038/nature14664
George J, Lim JS, Jang SJ, Cun Y, Ozretic L, Kong G, Leenders F, Lu X, Fernandez-Cuesta L, Bosco G, Mueller C, Dahmen I, Jahchan NS, Park K, Yang D, Karnezis AN, Vaka D, Torres A, Wang MS, Korbel JO, Menon R, Chun S, Kim D, Wilkerson M, Hayes N, Engelmann D, Puetzer B, Bos M, Michels S, Vlasic I, Seidel D, Pinther B, Schaub P, Becker C, Altmueller 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 C, Kim Y, 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, Knežević J, Castanos-Velez E, Roz L, Pastorino U, Brustugun O, Lund-Iversen M, Thunnissen E, Koehler J, Schuler M, Botling J, Sandelin M, Sanchez-Cespedes M, Salvesen HB, Achter V, Lang U, Bogus M, Schneider PM, Zander T, Ansen S, Hallek M, Wolf J, Vingron M, Yatabe Y, Travis WD, Nuernberg P, Reinhardt C, Perner S, Heukamp L, Buettner R, Haas SA, Brambilla E, Peifer M, Sage J, Thomas RK. Comprehensive genomic profiles of small cell lung cancer. in Nature. 2015;524(7563):47-53. doi:10.1038/nature14664 .
George, Julie, Lim, Jing Shan, Jang, Se Jin, Cun, Yupeng, Ozretic, Luka, Kong, Gu, Leenders, Frauke, Lu, Xin, Fernandez-Cuesta, Lynnette, Bosco, Graziella, Mueller, 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, Puetzer, Brigitte, Bos, Marc, Michels, Sebastian, Vlasic, Ignacija, Seidel, Danila, 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, 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, Knežević, Jelena, Castanos-Velez, Esmeralda, Roz, Luca, Pastorino, Ugo, Brustugun, Odd-Terje, Lund-Iversen, Marius, Thunnissen, Erik, Koehler, Jens, Schuler, Martin, Botling, Johan, Sandelin, Martin, Sanchez-Cespedes, Montserrat, Salvesen, Helga B., Achter, Viktor, Lang, Ulrich, Bogus, Magdalena, Schneider, Peter M., Zander, Thomas, Ansen, Sascha, Hallek, Michael, Wolf, Juergen, Vingron, Martin, Yatabe, Yasushi, Travis, William D., Nuernberg, Peter, Reinhardt, Christian, Perner, Sven, Heukamp, Lukas, Buettner, Reinhard, Haas, Stefan A., Brambilla, Elisabeth, Peifer, Martin, Sage, Julien, Thomas, Roman K., "Comprehensive genomic profiles of small cell lung cancer" in Nature, 524, no. 7563 (2015):47-53, https://doi.org/10.1038/nature14664 . .