Frequent mutations in chromatin-remodelling genes in pulmonary carcinoids

Lynnette Fernandez-Cuesta; Martin Peifer; Xin Lu; Ruping Sun; Luka Ozretić; Danila Seidel; Thomas Zander; Frauke Leenders; Julie George; Christian Müller; Ilona Dahmen; Berit Pinther; Graziella Bosco; Kathryn Konrad; Janine Altmüller; Peter Nürnberg; Viktor Achter; Ulrich Lang; Peter M. Schneider; Magdalena Bogus; Alex Soltermann; Odd T.erje Brustugun; Åslaug Helland; Steinar Solberg; Marius Lund-Iversen; Sascha Ansén; Erich Stoelben; Gavin M. Wright; Prudence Russell; Zoe Wainer; Benjamin Solomon; John K. Field; Russell Hyde; Michael P.A. Davies; Lukas C. Heukamp; Iver Petersen; Sven Perner; Christine M. Lovly; Federico Cappuzzo; William D. Travis; Jürgen Wolf; Martin Vingron; Elisabeth Brambilla; Stefan A. Haas; Reinhard Buettner; Roman K. Thomas

doi:10.1038/ncomms4518

Frequent mutations in chromatin-remodelling genes in pulmonary carcinoids

Lynnette Fernandez-Cuesta, Martin Peifer, Xin Lu, Ruping Sun, Luka Ozretić, Danila Seidel, Thomas Zander, Frauke Leenders, Julie George, Christian Müller, Ilona Dahmen, Berit Pinther, Graziella Bosco, Kathryn Konrad, Janine Altmüller, Peter Nürnberg, Viktor Achter, Ulrich Lang, Peter M. Schneider, Magdalena BogusAlex Soltermann, Odd T.erje Brustugun, Åslaug Helland, Steinar Solberg, Marius Lund-Iversen, Sascha Ansén, Erich Stoelben, Gavin M. Wright, Prudence Russell, Zoe Wainer, Benjamin Solomon, John K. Field, Russell Hyde, Michael P.A. Davies, Lukas C. Heukamp, Iver Petersen, Sven Perner, Christine M. Lovly, Federico Cappuzzo, William D. Travis, Jürgen Wolf, Martin Vingron, Elisabeth Brambilla, Stefan A. Haas, Reinhard Buettner, Roman K. Thomas

Institute of Pathology

162 Citations (Scopus)

Abstract

Pulmonary carcinoids are rare neuroendocrine tumours of the lung. The molecular alterations underlying the pathogenesis of these tumours have not been systematically studied so far. Here we perform gene copy number analysis (n=54), genome/exome (n=44) and transcriptome (n=69) sequencing of pulmonary carcinoids and observe frequent mutations in chromatin-remodelling genes. Covalent histone modifiers and subunits of the SWI/SNF complex are mutated in 40 and 22.2% of the cases, respectively, with MEN1, PSIP1 and ARID1A being recurrently affected. In contrast to small-cell lung cancer and large-cell neuroendocrine lung tumours, TP53 and RB1 mutations are rare events, suggesting that pulmonary carcinoids are not early progenitor lesions of the highly aggressive lung neuroendocrine tumours but arise through independent cellular mechanisms. These data also suggest that inactivation of chromatin-remodelling genes is sufficient to drive transformation in pulmonary carcinoids.

Original language	English
Article number	3518
Journal	Nature Communications
Volume	5
Pages (from-to)	3518
Number of pages	1
ISSN	1751-8628
DOIs	https://doi.org/10.1038/ncomms4518
Publication status	Published - 03.2014

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Fernandez-Cuesta, L., Peifer, M., Lu, X., Sun, R., Ozretić, L., Seidel, D., Zander, T., Leenders, F., George, J., Müller, C., Dahmen, I., Pinther, B., Bosco, G., Konrad, K., Altmüller, J., Nürnberg, P., Achter, V., Lang, U., Schneider, P. M., ... Thomas, R. K. (2014). Frequent mutations in chromatin-remodelling genes in pulmonary carcinoids. Nature Communications, 5, 3518. Article 3518. https://doi.org/10.1038/ncomms4518

@article{5e8ac42945964f1e9e73205b0bd50cb8,

title = "Frequent mutations in chromatin-remodelling genes in pulmonary carcinoids",

abstract = "Pulmonary carcinoids are rare neuroendocrine tumours of the lung. The molecular alterations underlying the pathogenesis of these tumours have not been systematically studied so far. Here we perform gene copy number analysis (n=54), genome/exome (n=44) and transcriptome (n=69) sequencing of pulmonary carcinoids and observe frequent mutations in chromatin-remodelling genes. Covalent histone modifiers and subunits of the SWI/SNF complex are mutated in 40 and 22.2% of the cases, respectively, with MEN1, PSIP1 and ARID1A being recurrently affected. In contrast to small-cell lung cancer and large-cell neuroendocrine lung tumours, TP53 and RB1 mutations are rare events, suggesting that pulmonary carcinoids are not early progenitor lesions of the highly aggressive lung neuroendocrine tumours but arise through independent cellular mechanisms. These data also suggest that inactivation of chromatin-remodelling genes is sufficient to drive transformation in pulmonary carcinoids. ",

author = "Lynnette Fernandez-Cuesta and Martin Peifer and Xin Lu and Ruping Sun and Luka Ozreti{\'c} and Danila Seidel and Thomas Zander and Frauke Leenders and Julie George and Christian M{\"u}ller and Ilona Dahmen and Berit Pinther and Graziella Bosco and Kathryn Konrad and Janine Altm{\"u}ller and Peter N{\"u}rnberg and Viktor Achter and Ulrich Lang and Schneider, {Peter M.} and Magdalena Bogus and Alex Soltermann and Brustugun, {Odd T.erje} and {\AA}slaug Helland and Steinar Solberg and Marius Lund-Iversen and Sascha Ans{\'e}n and Erich Stoelben and Wright, {Gavin M.} and Prudence Russell and Zoe Wainer and Benjamin Solomon and Field, {John K.} and Russell Hyde and Davies, {Michael P.A.} and Heukamp, {Lukas C.} and Iver Petersen and Sven Perner and Lovly, {Christine M.} and Federico Cappuzzo and Travis, {William D.} and J{\"u}rgen Wolf and Martin Vingron and Elisabeth Brambilla and Haas, {Stefan A.} and Reinhard Buettner and Thomas, {Roman K.}",

note = "Funding Information: We are indebted to the patients donating their tumour specimens as part of the Clinical Lung Cancer Genome Project initiative. We thank Philipp Lorimier, Elisabeth Kirst, Emilia M{\"u}ller and Juana Cuesta Valdes for their technical assistance. We furthermore thank the regional computing centre of the University of Cologne (RRZK) for providing the CPU time on the DFG-funded supercomputer {\textquoteleft}CHEOPS{\textquoteright}, as well as the support. This work was supported by the 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.). Additional funds were provided by the EU-Framework program CURELUNG (HEALTH-F2-2010-258677 to R.K.T., J.W., J.K.F. and E.B.); by the German federal state North Rhine Westphalia (NRW) and the European Union (European Regional Development Fund: Investing In Your Future) within PerMed NRW (grant 005-1111-0025 to R.K.T., J.W., R.B.); by the Deutsche Forschungsgemeinschaft through TH1386/3-1 (to R.K.T.) and through SFB832 (TP6 to R.K.T. and J.W.; TP5 to L.C.H.); by the German Ministry of Science and Education (BMBF) as part of the NGFNplus program (grant 01GS08101 to R.K.T., J.W., P.N.); by the Deutsche Krebshilfe as part of the Oncology Centers of Excellence funding program (R.K.T., R.B., J.W.); by Stand Up To Cancer– American Association for Cancer Research Innovative Research Grant (SU2C-AACR-IR60109 to R.K.T.); by an NIH K12 training grant (K12 CA9060625) and by an Uniting Against Lung Cancer grant, and a Damon Runyon Clinical Investigator Award (to C.M.L.); and by AIRC and Istituto Toscano Tumori project F13/16 (to F.C.). Copyright: This record is sourced from MEDLINE/PubMed, a database of the U.S. National Library of Medicine",

year = "2014",

month = mar,

doi = "10.1038/ncomms4518",

language = "English",

volume = "5",

pages = "3518",

journal = "Nature Communications",

issn = "1751-8628",

}

Fernandez-Cuesta, L, Peifer, M, Lu, X, Sun, R, Ozretić, L, Seidel, D, Zander, T, Leenders, F, George, J, Müller, C, Dahmen, I, Pinther, B, Bosco, G, Konrad, K, Altmüller, J, Nürnberg, P, Achter, V, Lang, U, Schneider, PM, Bogus, M, Soltermann, A, Brustugun, OTE, Helland, Å, Solberg, S, Lund-Iversen, M, Ansén, S, Stoelben, E, Wright, GM, Russell, P, Wainer, Z, Solomon, B, Field, JK, Hyde, R, Davies, MPA, Heukamp, LC, Petersen, I, Perner, S, Lovly, CM, Cappuzzo, F, Travis, WD, Wolf, J, Vingron, M, Brambilla, E, Haas, SA, Buettner, R & Thomas, RK 2014, 'Frequent mutations in chromatin-remodelling genes in pulmonary carcinoids', Nature Communications, vol. 5, 3518, pp. 3518. https://doi.org/10.1038/ncomms4518

TY - JOUR

T1 - Frequent mutations in chromatin-remodelling genes in pulmonary carcinoids

AU - Fernandez-Cuesta, Lynnette

AU - Peifer, Martin

AU - Lu, Xin

AU - Sun, Ruping

AU - Ozretić, Luka

AU - Seidel, Danila

AU - Zander, Thomas

AU - Leenders, Frauke

AU - George, Julie

AU - Müller, Christian

AU - Dahmen, Ilona

AU - Pinther, Berit

AU - Bosco, Graziella

AU - Konrad, Kathryn

AU - Altmüller, Janine

AU - Nürnberg, Peter

AU - Achter, Viktor

AU - Lang, Ulrich

AU - Schneider, Peter M.

AU - Bogus, Magdalena

AU - Soltermann, Alex

AU - Brustugun, Odd T.erje

AU - Helland, Åslaug

AU - Solberg, Steinar

AU - Lund-Iversen, Marius

AU - Ansén, Sascha

AU - Stoelben, Erich

AU - Wright, Gavin M.

AU - Russell, Prudence

AU - Wainer, Zoe

AU - Solomon, Benjamin

AU - Field, John K.

AU - Hyde, Russell

AU - Davies, Michael P.A.

AU - Heukamp, Lukas C.

AU - Petersen, Iver

AU - Perner, Sven

AU - Lovly, Christine M.

AU - Cappuzzo, Federico

AU - Travis, William D.

AU - Wolf, Jürgen

AU - Vingron, Martin

AU - Brambilla, Elisabeth

AU - Haas, Stefan A.

AU - Buettner, Reinhard

AU - Thomas, Roman K.

N1 - Funding Information: We are indebted to the patients donating their tumour specimens as part of the Clinical Lung Cancer Genome Project initiative. We thank Philipp Lorimier, Elisabeth Kirst, Emilia Müller and Juana Cuesta Valdes for their technical assistance. We furthermore thank the regional computing centre of the University of Cologne (RRZK) for providing the CPU time on the DFG-funded supercomputer ‘CHEOPS’, as well as the support. This work was supported by the 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.). Additional funds were provided by the EU-Framework program CURELUNG (HEALTH-F2-2010-258677 to R.K.T., J.W., J.K.F. and E.B.); by the German federal state North Rhine Westphalia (NRW) and the European Union (European Regional Development Fund: Investing In Your Future) within PerMed NRW (grant 005-1111-0025 to R.K.T., J.W., R.B.); by the Deutsche Forschungsgemeinschaft through TH1386/3-1 (to R.K.T.) and through SFB832 (TP6 to R.K.T. and J.W.; TP5 to L.C.H.); by the German Ministry of Science and Education (BMBF) as part of the NGFNplus program (grant 01GS08101 to R.K.T., J.W., P.N.); by the Deutsche Krebshilfe as part of the Oncology Centers of Excellence funding program (R.K.T., R.B., J.W.); by Stand Up To Cancer– American Association for Cancer Research Innovative Research Grant (SU2C-AACR-IR60109 to R.K.T.); by an NIH K12 training grant (K12 CA9060625) and by an Uniting Against Lung Cancer grant, and a Damon Runyon Clinical Investigator Award (to C.M.L.); and by AIRC and Istituto Toscano Tumori project F13/16 (to F.C.). Copyright: This record is sourced from MEDLINE/PubMed, a database of the U.S. National Library of Medicine

PY - 2014/3

Y1 - 2014/3

N2 - Pulmonary carcinoids are rare neuroendocrine tumours of the lung. The molecular alterations underlying the pathogenesis of these tumours have not been systematically studied so far. Here we perform gene copy number analysis (n=54), genome/exome (n=44) and transcriptome (n=69) sequencing of pulmonary carcinoids and observe frequent mutations in chromatin-remodelling genes. Covalent histone modifiers and subunits of the SWI/SNF complex are mutated in 40 and 22.2% of the cases, respectively, with MEN1, PSIP1 and ARID1A being recurrently affected. In contrast to small-cell lung cancer and large-cell neuroendocrine lung tumours, TP53 and RB1 mutations are rare events, suggesting that pulmonary carcinoids are not early progenitor lesions of the highly aggressive lung neuroendocrine tumours but arise through independent cellular mechanisms. These data also suggest that inactivation of chromatin-remodelling genes is sufficient to drive transformation in pulmonary carcinoids.

AB - Pulmonary carcinoids are rare neuroendocrine tumours of the lung. The molecular alterations underlying the pathogenesis of these tumours have not been systematically studied so far. Here we perform gene copy number analysis (n=54), genome/exome (n=44) and transcriptome (n=69) sequencing of pulmonary carcinoids and observe frequent mutations in chromatin-remodelling genes. Covalent histone modifiers and subunits of the SWI/SNF complex are mutated in 40 and 22.2% of the cases, respectively, with MEN1, PSIP1 and ARID1A being recurrently affected. In contrast to small-cell lung cancer and large-cell neuroendocrine lung tumours, TP53 and RB1 mutations are rare events, suggesting that pulmonary carcinoids are not early progenitor lesions of the highly aggressive lung neuroendocrine tumours but arise through independent cellular mechanisms. These data also suggest that inactivation of chromatin-remodelling genes is sufficient to drive transformation in pulmonary carcinoids.

UR - http://www.scopus.com/inward/record.url?scp=84902284546&partnerID=8YFLogxK

U2 - 10.1038/ncomms4518

DO - 10.1038/ncomms4518

M3 - Journal articles

C2 - 24670920

AN - SCOPUS:84902284546

SN - 1751-8628

VL - 5

SP - 3518

JO - Nature Communications

JF - Nature Communications

M1 - 3518

ER -

Frequent mutations in chromatin-remodelling genes in pulmonary carcinoids

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