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Title: Integrative genomic profiling of large-cell neuroendocrine carcinomas reveals distinct subtypes of high-grade neuroendocrine lung tumors

Abstract

Pulmonary large-cell neuroendocrine carcinomas (LCNECs) have similarities with other lung cancers, but their precise relationship has remained unclear. Here in this paper we perform a comprehensive genomic (n = 60) and transcriptomic (n = 69) analysis of 75 LCNECs and identify two molecular subgroups: “type I LCNECs” with bi-allelic TP53 and STK11/KEAP1 alterations (37%), and “type II LCNECs” enriched for bi-allelic inactivation of TP53 and RB1 (42%). Despite sharing genomic alterations with adenocarcinomas and squamous cell carcinomas, no transcriptional relationship was found; instead LCNECs form distinct transcriptional subgroups with closest similarity to SCLC. While type I LCNECs and SCLCs exhibit a neuroendocrine profile with ASCL1 high/DLL3 high/NOTCH low, type II LCNECs bear TP53 and RB1 alterations and differ from most SCLC tumors with reduced neuroendocrine markers, a pattern of ASCL1 low/DLL3 low/NOTCH high, and an upregulation of immune-related pathways. In conclusion, LCNECs comprise two molecularly defined subgroups, and distinguishing them from SCLC may allow stratified targeted treatment of high-grade neuroendocrine lung tumors.

Authors:
 [1];  [2]; ORCiD logo [1]; ORCiD logo [3];  [1];  [1];  [1];  [1];  [1];  [4];  [4];  [4];  [4]; ORCiD logo [5];  [6];  [7];  [1];  [1];  [8];  [9] more »;  [10];  [1];  [1];  [1]; ORCiD logo [10];  [10];  [11];  [11]; ORCiD logo [1];  [4];  [12];  [12];  [13];  [12];  [14];  [14];  [14];  [15];  [16];  [14];  [16];  [10]; ORCiD logo [17];  [18];  [19];  [19];  [20];  [20];  [21];  [10]; ORCiD logo [22];  [10];  [23];  [24];  [22];  [4];  [4];  [10];  [11];  [12];  [25];  [26] « less
  1. Univ. of Cologne (Germany)
  2. Univ. of North Carolina, Chapel Hill, NC (United States); Penn State Milton S. Hershey Medical Center, Hershey, PA (United States)
  3. Univ. of California, San Diego, CA (United States)
  4. International Agency for Research on Cancer (IARC-WHO), Lyon (France)
  5. Max Planck Inst. for Molecular Genetics, Berlin (Germany)
  6. Programme Cartes d’Identité des Tumeurs (CIT), Ligue Nationale Contre le Cancer Paris (France)
  7. Centre Hospitalier Universitaire (CHU) de Grenoble, Genoble (France)
  8. NEO New Oncology GmbH, Cologne (Germany)
  9. Univ. of Cologne (Germany); University Hospital Cologne, Cologne (Germany)
  10. University Hospital Cologne, Cologne (Germany)
  11. Univ. of North Carolina, Chapel Hill, NC (United States)
  12. Univ. de Grenoble Alpes, Grenoble (France)
  13. Univ. de Grenoble Alpes, Grenoble (France); Centre Leon Berard UNICANCER, Lyon (France)
  14. Univ. Hospital Zurich, Zurich (Switzerland)
  15. Univ. of Oslo (Norway); Oslo Univ. Hospital, Oslo (Norway)
  16. Oslo Univ. Hospital, Oslo (Norway)
  17. St. Vincent’s Hospital, Melbourne, VIC (Australia)
  18. Peter MacCallum Cancer Centre, Melbourne, VIC (Australia)
  19. Fondazione IRCCS-Istituto Nazionale Tumori, Milan (Italy)
  20. Friedrich Schiller Univ., Jena (Germany)
  21. Institute for Pathology Bad Berka, Bad Berka (Germany)
  22. Max Planck Inst. for Molecular Genetics, Berlin(Germany)
  23. Univ. Medical Center Schleswig-Holstein, Luebeck, Borstel (Germany)
  24. Memorial Sloan-Kettering Cancer Center, New York, NY (United States)
  25. Univ. of Cologne (Germany); International Agency for Research on Cancer (IARC-WHO), Lyon (France)
  26. Univ. of Cologne (Germany); University Hospital Cologne, Cologne (Germany); German Cancer Research Center, German Cancer Consortium (DKTK), Heidelberg (Germany)
Publication Date:
Research Org.:
Los Alamos National Lab. (LANL), Los Alamos, NM (United States)
Sponsoring Org.:
USDOE Laboratory Directed Research and Development (LDRD) Program
OSTI Identifier:
1460632
Report Number(s):
LA-UR-16-29056
Journal ID: ISSN 2041-1723
Grant/Contract Number:  
AC52-06NA25396
Resource Type:
Accepted Manuscript
Journal Name:
Nature Communications
Additional Journal Information:
Journal Volume: 9; Journal Issue: 1; Journal ID: ISSN 2041-1723
Publisher:
Nature Publishing Group
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES; Biological Science

Citation Formats

George, Julie, Walter, Vonn, Peifer, Martin, Alexandrov, Ludmil B., Seidel, Danila, Leenders, Frauke, Maas, Lukas, Muller, Christian, Dahmen, Ilona, Delhomme, Tiffany M., Ardin, Maude, Leblay, Noemie, Byrnes, Graham, Sun, Ruping, De Reynies, Aurelien, McLeer-Florin, Anne, Bosco, Graziella, Malchers, Florian, Menon, Roopika, Altmuller, Janine, Becker, Christian, Nurnberg, Peter, Achter, Viktor, Lang, Ulrich, Schneider, Peter M., Bogus, Magdalena, Soloway, Matthew G., Wilkerson, Matthew D., Cun, Yupeng, McKay, James D., Moro-Sibilot, Denis, Brambilla, Christian G., Lantuejoul, Sylvie, Lemaitre, Nicolas, Soltermann, Alex, Weder, Walter, Tischler, Verena, Brustugun, Odd Terje, Lund-Iversen, Marius, Helland, Aslaug, Solberg, Steinar, Ansen, Sascha, Wright, Gavin, Solomon, Benjamin, Roz, Luca, Pastorino, Ugo, Petersen, Iver, Clement, Joachim H., Sanger, Jorg, Wolf, Jurgen, Vingron, Martin, Zander, Thomas, Perner, Sven, Travis, William D., Haas, Stefan A., Olivier, Magali, Foll, Matthieu, Buttner, Reinhard, Hayes, David Neil, Brambilla, Elisabeth, Fernandez-Cuesta, Lynnette, and Thomas, Roman K. Integrative genomic profiling of large-cell neuroendocrine carcinomas reveals distinct subtypes of high-grade neuroendocrine lung tumors. United States: N. p., 2018. Web. doi:10.1038/s41467-018-03099-x.
George, Julie, Walter, Vonn, Peifer, Martin, Alexandrov, Ludmil B., Seidel, Danila, Leenders, Frauke, Maas, Lukas, Muller, Christian, Dahmen, Ilona, Delhomme, Tiffany M., Ardin, Maude, Leblay, Noemie, Byrnes, Graham, Sun, Ruping, De Reynies, Aurelien, McLeer-Florin, Anne, Bosco, Graziella, Malchers, Florian, Menon, Roopika, Altmuller, Janine, Becker, Christian, Nurnberg, Peter, Achter, Viktor, Lang, Ulrich, Schneider, Peter M., Bogus, Magdalena, Soloway, Matthew G., Wilkerson, Matthew D., Cun, Yupeng, McKay, James D., Moro-Sibilot, Denis, Brambilla, Christian G., Lantuejoul, Sylvie, Lemaitre, Nicolas, Soltermann, Alex, Weder, Walter, Tischler, Verena, Brustugun, Odd Terje, Lund-Iversen, Marius, Helland, Aslaug, Solberg, Steinar, Ansen, Sascha, Wright, Gavin, Solomon, Benjamin, Roz, Luca, Pastorino, Ugo, Petersen, Iver, Clement, Joachim H., Sanger, Jorg, Wolf, Jurgen, Vingron, Martin, Zander, Thomas, Perner, Sven, Travis, William D., Haas, Stefan A., Olivier, Magali, Foll, Matthieu, Buttner, Reinhard, Hayes, David Neil, Brambilla, Elisabeth, Fernandez-Cuesta, Lynnette, & Thomas, Roman K. Integrative genomic profiling of large-cell neuroendocrine carcinomas reveals distinct subtypes of high-grade neuroendocrine lung tumors. United States. doi:10.1038/s41467-018-03099-x.
George, Julie, Walter, Vonn, Peifer, Martin, Alexandrov, Ludmil B., Seidel, Danila, Leenders, Frauke, Maas, Lukas, Muller, Christian, Dahmen, Ilona, Delhomme, Tiffany M., Ardin, Maude, Leblay, Noemie, Byrnes, Graham, Sun, Ruping, De Reynies, Aurelien, McLeer-Florin, Anne, Bosco, Graziella, Malchers, Florian, Menon, Roopika, Altmuller, Janine, Becker, Christian, Nurnberg, Peter, Achter, Viktor, Lang, Ulrich, Schneider, Peter M., Bogus, Magdalena, Soloway, Matthew G., Wilkerson, Matthew D., Cun, Yupeng, McKay, James D., Moro-Sibilot, Denis, Brambilla, Christian G., Lantuejoul, Sylvie, Lemaitre, Nicolas, Soltermann, Alex, Weder, Walter, Tischler, Verena, Brustugun, Odd Terje, Lund-Iversen, Marius, Helland, Aslaug, Solberg, Steinar, Ansen, Sascha, Wright, Gavin, Solomon, Benjamin, Roz, Luca, Pastorino, Ugo, Petersen, Iver, Clement, Joachim H., Sanger, Jorg, Wolf, Jurgen, Vingron, Martin, Zander, Thomas, Perner, Sven, Travis, William D., Haas, Stefan A., Olivier, Magali, Foll, Matthieu, Buttner, Reinhard, Hayes, David Neil, Brambilla, Elisabeth, Fernandez-Cuesta, Lynnette, and Thomas, Roman K. Tue . "Integrative genomic profiling of large-cell neuroendocrine carcinomas reveals distinct subtypes of high-grade neuroendocrine lung tumors". United States. doi:10.1038/s41467-018-03099-x. https://www.osti.gov/servlets/purl/1460632.
@article{osti_1460632,
title = {Integrative genomic profiling of large-cell neuroendocrine carcinomas reveals distinct subtypes of high-grade neuroendocrine lung tumors},
author = {George, Julie and Walter, Vonn and Peifer, Martin and Alexandrov, Ludmil B. and Seidel, Danila and Leenders, Frauke and Maas, Lukas and Muller, Christian and Dahmen, Ilona and Delhomme, Tiffany M. and Ardin, Maude and Leblay, Noemie and Byrnes, Graham and Sun, Ruping and De Reynies, Aurelien and McLeer-Florin, Anne and Bosco, Graziella and Malchers, Florian and Menon, Roopika and Altmuller, Janine and Becker, Christian and Nurnberg, Peter and Achter, Viktor and Lang, Ulrich and Schneider, Peter M. and Bogus, Magdalena and Soloway, Matthew G. and Wilkerson, Matthew D. and Cun, Yupeng and McKay, James D. and Moro-Sibilot, Denis and Brambilla, Christian G. and Lantuejoul, Sylvie and Lemaitre, Nicolas and Soltermann, Alex and Weder, Walter and Tischler, Verena and Brustugun, Odd Terje and Lund-Iversen, Marius and Helland, Aslaug and Solberg, Steinar and Ansen, Sascha and Wright, Gavin and Solomon, Benjamin and Roz, Luca and Pastorino, Ugo and Petersen, Iver and Clement, Joachim H. and Sanger, Jorg and Wolf, Jurgen and Vingron, Martin and Zander, Thomas and Perner, Sven and Travis, William D. and Haas, Stefan A. and Olivier, Magali and Foll, Matthieu and Buttner, Reinhard and Hayes, David Neil and Brambilla, Elisabeth and Fernandez-Cuesta, Lynnette and Thomas, Roman K.},
abstractNote = {Pulmonary large-cell neuroendocrine carcinomas (LCNECs) have similarities with other lung cancers, but their precise relationship has remained unclear. Here in this paper we perform a comprehensive genomic (n = 60) and transcriptomic (n = 69) analysis of 75 LCNECs and identify two molecular subgroups: “type I LCNECs” with bi-allelic TP53 and STK11/KEAP1 alterations (37%), and “type II LCNECs” enriched for bi-allelic inactivation of TP53 and RB1 (42%). Despite sharing genomic alterations with adenocarcinomas and squamous cell carcinomas, no transcriptional relationship was found; instead LCNECs form distinct transcriptional subgroups with closest similarity to SCLC. While type I LCNECs and SCLCs exhibit a neuroendocrine profile with ASCL1high/DLL3high/NOTCHlow, type II LCNECs bear TP53 and RB1 alterations and differ from most SCLC tumors with reduced neuroendocrine markers, a pattern of ASCL1low/DLL3low/NOTCHhigh, and an upregulation of immune-related pathways. In conclusion, LCNECs comprise two molecularly defined subgroups, and distinguishing them from SCLC may allow stratified targeted treatment of high-grade neuroendocrine lung tumors.},
doi = {10.1038/s41467-018-03099-x},
journal = {Nature Communications},
number = 1,
volume = 9,
place = {United States},
year = {2018},
month = {3}
}

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Significance analysis of microarrays applied to the ionizing radiation response
journal, April 2001

  • Tusher, V. G.; Tibshirani, R.; Chu, G.
  • Proceedings of the National Academy of Sciences, Vol. 98, Issue 9, p. 5116-5121
  • DOI: 10.1073/pnas.091062498