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

Julie George; Vonn Walter; Martin Peifer; Ludmil B. Alexandrov; Danila Seidel; Frauke Leenders; Lukas Maas; Christian Müller; Ilona Dahmen; Tiffany M. Delhomme; Maude Ardin; Noemie Leblay; Graham Byrnes; Ruping Sun; Aurélien De Reynies; Anne McLeer-Florin; Graziella Bosco; Florian Malchers; Roopika Menon; Janine Altmüller; Christian Becker; Peter Nürnberg; Viktor Achter; Ulrich Lang; Peter M. Schneider; Magdalena Bogus; Matthew G. Soloway; Matthew D. Wilkerson; Yupeng Cun; James D. McKay; Denis Moro-Sibilot; Christian G. Brambilla; Sylvie Lantuejoul; Nicolas Lemaitre; Alex Soltermann; Walter Weder; Verena Tischler; Odd Terje Brustugun; Marius Lund-Iversen; Åslaug Helland; Steinar Solberg; Sascha Ansén; Gavin Wright; Benjamin Solomon; Luca Roz; Ugo Pastorino; Iver Petersen; Joachim H. Clement; Jörg Sänger; Jürgen Wolf; Martin Vingron; Thomas Zander; Sven Perner; William D. Travis; Stefan A. Haas; Magali Olivier; Matthieu Foll; Reinhard Büttner; David Neil Hayes; Elisabeth Brambilla; Lynnette Fernandez-Cuesta; Roman K. Thomas

doi:10.1038/s41467-018-03099-x

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

Julie George, Vonn Walter, Martin Peifer, Ludmil B. Alexandrov, Danila Seidel, Frauke Leenders, Lukas Maas, Christian Müller, Ilona Dahmen, Tiffany M. Delhomme, Maude Ardin, Noemie Leblay, Graham Byrnes, Ruping Sun, Aurélien De Reynies, Anne McLeer-Florin, Graziella Bosco, Florian Malchers, Roopika Menon, Janine AltmüllerChristian Becker, Peter Nürnberg, Viktor Achter, Ulrich Lang, Peter M. Schneider, Magdalena Bogus, Matthew G. Soloway, Matthew D. Wilkerson, Yupeng Cun, James D. McKay, Denis Moro-Sibilot, Christian G. Brambilla, Sylvie Lantuejoul, Nicolas Lemaitre, Alex Soltermann, Walter Weder, Verena Tischler, Odd Terje Brustugun, Marius Lund-Iversen, Åslaug Helland, Steinar Solberg, Sascha Ansén, Gavin Wright, Benjamin Solomon, Luca Roz, Ugo Pastorino, Iver Petersen, Joachim H. Clement, Jörg Sänger, Jürgen Wolf, Martin Vingron, Thomas Zander, Sven Perner, William D. Travis, Stefan A. Haas, Magali Olivier, Matthieu Foll, Reinhard Büttner, David Neil Hayes, Elisabeth Brambilla, Lynnette Fernandez-Cuesta, Roman K. Thomas

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Abstract

Pulmonary large-cell neuroendocrine carcinomas (LCNECs) have similarities with other lung cancers, but their precise relationship has remained unclear. Here 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.

Original language	English (US)
Article number	1048
Journal	Nature communications
Volume	9
Issue number	1
DOIs	https://doi.org/10.1038/s41467-018-03099-x
State	Published - Dec 1 2018
Externally published	Yes

Bibliographical note

Funding Information:
This work was supported by the German Cancer Aid (Deutsche Krebshilfe) as part of the small cell lung cancer genome sequencing consortium (grant ID: 109679 to R.K.T., M.P., R.B., P.N., M.V., and S.A.H.), by the German Ministry of Science and Education (BMBF) as part of the e:Med program (grant no. 01ZX1303A to R.K.T., R.B., U.L., M.P. and J. W, and grant no. 01ZX1406 to M.P.), by the EU-Framework program CURELUNG (HEALTH-F2-2010-258677 to R.K.T., J.W., E.B., and L.R.), by the Deutsche For-schungsgemeinschaft (DFG; through TH1386/3-1 to R.K.T.), by the Deutsche Krebshilfe as part of the Oncology Centers of Excellence funding program (R.K.T.), by the National Institute of Health (NIH U10CA181009 to D.N.H.), by the German Cancer Consortium (DKTK) Joint Funding program, by Associazione Italiana per la Ricerca sul Cancro (AIRC, IG 16847 to L.R.), and by the Los Alamos National Laboratory Institutional Computing Program, which is supported by the U.S. Department of Energy National Nuclear Security Administration under Contract No. DE-AC52-06NA25396 (L.B.A.). J. G. received funding as part of the IASLC Young Investigator award. L.B.A. is supported through a J. Robert Oppenheimer Fellowship at Los Alamos National Laboratory. We are indebted to the patients donating their tumor specimens as part of the Clinical Lung Cancer Genome Project initiative. We thank the regional computing center of the University of Cologne (RRZK) for providing the CPU time on the DFG-funded supercomputer ‘CHEOPS’, as well as the support. We would like to acknowledge that Australian specimens were provided with assistance of the Victorian Cancer Biobank. We furthermore thank Johannes Berg, Chau Nguyen, Philipp Lorimier, Elisabeth Kirst, and César Tejerina Álvarez for their technical assistance.

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© 2018 The Author(s).

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George, J., Walter, V., Peifer, M., Alexandrov, L. B., Seidel, D., Leenders, F., Maas, L., Müller, C., Dahmen, I., Delhomme, T. M., Ardin, M., Leblay, N., Byrnes, G., Sun, R., De Reynies, A., McLeer-Florin, A., Bosco, G., Malchers, F., Menon, R., ... Thomas, R. K. (2018). Integrative genomic profiling of large-cell neuroendocrine carcinomas reveals distinct subtypes of high-grade neuroendocrine lung tumors. Nature communications, 9(1), Article 1048. https://doi.org/10.1038/s41467-018-03099-x

George, J, Walter, V, Peifer, M, Alexandrov, LB, Seidel, D, Leenders, F, Maas, L, Müller, C, Dahmen, I, Delhomme, TM, Ardin, M, Leblay, N, Byrnes, G, Sun, R, De Reynies, A, McLeer-Florin, A, Bosco, G, Malchers, F, Menon, R, Altmüller, J, Becker, C, Nürnberg, P, Achter, V, Lang, U, Schneider, PM, Bogus, M, Soloway, MG, Wilkerson, MD, Cun, Y, McKay, JD, Moro-Sibilot, D, Brambilla, CG, Lantuejoul, S, Lemaitre, N, Soltermann, A, Weder, W, Tischler, V, Brustugun, OT, Lund-Iversen, M, Helland, Å, Solberg, S, Ansén, S, Wright, G, Solomon, B, Roz, L, Pastorino, U, Petersen, I, Clement, JH, Sänger, J, Wolf, J, Vingron, M, Zander, T, Perner, S, Travis, WD, Haas, SA, Olivier, M, Foll, M, Büttner, R, Hayes, DN, Brambilla, E, Fernandez-Cuesta, L & Thomas, RK 2018, 'Integrative genomic profiling of large-cell neuroendocrine carcinomas reveals distinct subtypes of high-grade neuroendocrine lung tumors', Nature communications, vol. 9, no. 1, 1048. https://doi.org/10.1038/s41467-018-03099-x

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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 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.",

author = "Julie George and Vonn Walter and Martin Peifer and Alexandrov, {Ludmil B.} and Danila Seidel and Frauke Leenders and Lukas Maas and Christian M{\"u}ller and Ilona Dahmen and Delhomme, {Tiffany M.} and Maude Ardin and Noemie Leblay and Graham Byrnes and Ruping Sun and {De Reynies}, Aur{\'e}lien and Anne McLeer-Florin and Graziella Bosco and Florian Malchers and Roopika Menon and Janine Altm{\"u}ller and Christian Becker and Peter N{\"u}rnberg and Viktor Achter and Ulrich Lang and Schneider, {Peter M.} and Magdalena Bogus and Soloway, {Matthew G.} and Wilkerson, {Matthew D.} and Yupeng Cun and McKay, {James D.} and Denis Moro-Sibilot and Brambilla, {Christian G.} and Sylvie Lantuejoul and Nicolas Lemaitre and Alex Soltermann and Walter Weder and Verena Tischler and Brustugun, {Odd Terje} and Marius Lund-Iversen and {\AA}slaug Helland and Steinar Solberg and Sascha Ans{\'e}n and Gavin Wright and Benjamin Solomon and Luca Roz and Ugo Pastorino and Iver Petersen and Clement, {Joachim H.} and J{\"o}rg S{\"a}nger and J{\"u}rgen Wolf and Martin Vingron and Thomas Zander and Sven Perner and Travis, {William D.} and Haas, {Stefan A.} and Magali Olivier and Matthieu Foll and Reinhard B{\"u}ttner and Hayes, {David Neil} and Elisabeth Brambilla and Lynnette Fernandez-Cuesta and Thomas, {Roman K.}",

note = "Funding Information: This work was supported by the German Cancer Aid (Deutsche Krebshilfe) as part of the small cell lung cancer genome sequencing consortium (grant ID: 109679 to R.K.T., M.P., R.B., P.N., M.V., and S.A.H.), by the German Ministry of Science and Education (BMBF) as part of the e:Med program (grant no. 01ZX1303A to R.K.T., R.B., U.L., M.P. and J. W, and grant no. 01ZX1406 to M.P.), by the EU-Framework program CURELUNG (HEALTH-F2-2010-258677 to R.K.T., J.W., E.B., and L.R.), by the Deutsche For-schungsgemeinschaft (DFG; through TH1386/3-1 to R.K.T.), by the Deutsche Krebshilfe as part of the Oncology Centers of Excellence funding program (R.K.T.), by the National Institute of Health (NIH U10CA181009 to D.N.H.), by the German Cancer Consortium (DKTK) Joint Funding program, by Associazione Italiana per la Ricerca sul Cancro (AIRC, IG 16847 to L.R.), and by the Los Alamos National Laboratory Institutional Computing Program, which is supported by the U.S. Department of Energy National Nuclear Security Administration under Contract No. DE-AC52-06NA25396 (L.B.A.). J. G. received funding as part of the IASLC Young Investigator award. L.B.A. is supported through a J. Robert Oppenheimer Fellowship at Los Alamos National Laboratory. We are indebted to the patients donating their tumor specimens as part of the Clinical Lung Cancer Genome Project initiative. We thank the regional computing center of the University of Cologne (RRZK) for providing the CPU time on the DFG-funded supercomputer {\textquoteleft}CHEOPS{\textquoteright}, as well as the support. We would like to acknowledge that Australian specimens were provided with assistance of the Victorian Cancer Biobank. We furthermore thank Johannes Berg, Chau Nguyen, Philipp Lorimier, Elisabeth Kirst, and C{\'e}sar Tejerina {\'A}lvarez for their technical assistance. Publisher Copyright: {\textcopyright} 2018 The Author(s).",

year = "2018",

month = dec,

day = "1",

doi = "10.1038/s41467-018-03099-x",

language = "English (US)",

volume = "9",

journal = "Nature communications",

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publisher = "Nature Research",

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TY - JOUR

T1 - Integrative genomic profiling of large-cell neuroendocrine carcinomas reveals distinct subtypes of high-grade neuroendocrine lung tumors

AU - George, Julie

AU - Walter, Vonn

AU - Peifer, Martin

AU - Alexandrov, Ludmil B.

AU - Seidel, Danila

AU - Leenders, Frauke

AU - Maas, Lukas

AU - Müller, Christian

AU - Dahmen, Ilona

AU - Delhomme, Tiffany M.

AU - Ardin, Maude

AU - Leblay, Noemie

AU - Byrnes, Graham

AU - Sun, Ruping

AU - De Reynies, Aurélien

AU - McLeer-Florin, Anne

AU - Bosco, Graziella

AU - Malchers, Florian

AU - Menon, Roopika

AU - Altmüller, Janine

AU - Becker, Christian

AU - Nürnberg, Peter

AU - Achter, Viktor

AU - Lang, Ulrich

AU - Schneider, Peter M.

AU - Bogus, Magdalena

AU - Soloway, Matthew G.

AU - Wilkerson, Matthew D.

AU - Cun, Yupeng

AU - McKay, James D.

AU - Moro-Sibilot, Denis

AU - Brambilla, Christian G.

AU - Lantuejoul, Sylvie

AU - Lemaitre, Nicolas

AU - Soltermann, Alex

AU - Weder, Walter

AU - Tischler, Verena

AU - Brustugun, Odd Terje

AU - Lund-Iversen, Marius

AU - Helland, Åslaug

AU - Solberg, Steinar

AU - Ansén, Sascha

AU - Wright, Gavin

AU - Solomon, Benjamin

AU - Roz, Luca

AU - Pastorino, Ugo

AU - Petersen, Iver

AU - Clement, Joachim H.

AU - Sänger, Jörg

AU - Wolf, Jürgen

AU - Vingron, Martin

AU - Zander, Thomas

AU - Perner, Sven

AU - Travis, William D.

AU - Haas, Stefan A.

AU - Olivier, Magali

AU - Foll, Matthieu

AU - Büttner, Reinhard

AU - Hayes, David Neil

AU - Brambilla, Elisabeth

AU - Fernandez-Cuesta, Lynnette

AU - Thomas, Roman K.

N1 - Funding Information: This work was supported by the German Cancer Aid (Deutsche Krebshilfe) as part of the small cell lung cancer genome sequencing consortium (grant ID: 109679 to R.K.T., M.P., R.B., P.N., M.V., and S.A.H.), by the German Ministry of Science and Education (BMBF) as part of the e:Med program (grant no. 01ZX1303A to R.K.T., R.B., U.L., M.P. and J. W, and grant no. 01ZX1406 to M.P.), by the EU-Framework program CURELUNG (HEALTH-F2-2010-258677 to R.K.T., J.W., E.B., and L.R.), by the Deutsche For-schungsgemeinschaft (DFG; through TH1386/3-1 to R.K.T.), by the Deutsche Krebshilfe as part of the Oncology Centers of Excellence funding program (R.K.T.), by the National Institute of Health (NIH U10CA181009 to D.N.H.), by the German Cancer Consortium (DKTK) Joint Funding program, by Associazione Italiana per la Ricerca sul Cancro (AIRC, IG 16847 to L.R.), and by the Los Alamos National Laboratory Institutional Computing Program, which is supported by the U.S. Department of Energy National Nuclear Security Administration under Contract No. DE-AC52-06NA25396 (L.B.A.). J. G. received funding as part of the IASLC Young Investigator award. L.B.A. is supported through a J. Robert Oppenheimer Fellowship at Los Alamos National Laboratory. We are indebted to the patients donating their tumor specimens as part of the Clinical Lung Cancer Genome Project initiative. We thank the regional computing center of the University of Cologne (RRZK) for providing the CPU time on the DFG-funded supercomputer ‘CHEOPS’, as well as the support. We would like to acknowledge that Australian specimens were provided with assistance of the Victorian Cancer Biobank. We furthermore thank Johannes Berg, Chau Nguyen, Philipp Lorimier, Elisabeth Kirst, and César Tejerina Álvarez for their technical assistance. Publisher Copyright: © 2018 The Author(s).

PY - 2018/12/1

Y1 - 2018/12/1

N2 - Pulmonary large-cell neuroendocrine carcinomas (LCNECs) have similarities with other lung cancers, but their precise relationship has remained unclear. Here 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.

AB - Pulmonary large-cell neuroendocrine carcinomas (LCNECs) have similarities with other lung cancers, but their precise relationship has remained unclear. Here 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.

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U2 - 10.1038/s41467-018-03099-x

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JF - Nature communications

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ER -

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

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