Integrative and comparative genomic analyses identify clinically relevant pulmonary carcinoid groups and unveil the supra-carcinoids

N. Alcala, N. Leblay, A. A.G. Gabriel, L. Mangiante, D. Hervas, T. Giffon, A. S. Sertier, A. Ferrari, J. Derks, A. Ghantous, T. M. Delhomme, A. Chabrier, C. Cuenin, B. Abedi-Ardekani, A. Boland, R. Olaso, V. Meyer, J. Altmuller, F. Le Calvez-Kelm, G. DurandC. Voegele, S. Boyault, L. Moonen, N. Lemaitre, P. Lorimier, A. C. Toffart, A. Soltermann, J. H. Clement, J. Saenger, J. K. Field, M. Brevet, C. Blanc-Fournier, F. Galateau-Salle, N. Le Stang, P. A. Russell, G. Wright, G. Sozzi, U. Pastorino, S. Lacomme, J. M. Vignaud, V. Hofman, P. Hofman, O. T. Brustugun, M. Lund-Iversen, V. Thomas de Montpreville, L. A. Muscarella, P. Graziano, H. Popper, J. Stojsic, J. F. Deleuze, Z. Herceg, A. Viari, P. Nuernberg, G. Pelosi, A. M.C. Dingemans, M. Milione, L. Roz, L. Brcic, M. Volante, M. G. Papotti, C. Caux, J. Sandoval, H. Hernandez-Vargas, E. Brambilla, E. J.M. Speel, N. Girard, S. Lantuejoul, J. D. McKay, M. Foll, L. Fernandez-Cuesta*

*Corresponding author for this work

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Abstract

The worldwide incidence of pulmonary carcinoids is increasing, but little is known about their molecular characteristics. Through machine learning and multi-omics factor analysis, we compare and contrast the genomic profiles of 116 pulmonary carcinoids (including 35 atypical), 75 large-cell neuroendocrine carcinomas (LCNEC), and 66 small-cell lung cancers. Here we report that the integrative analyses on 257 lung neuroendocrine neoplasms stratify atypical carcinoids into two prognostic groups with a 10-year overall survival of 88% and 27%, respectively. We identify therapeutically relevant molecular groups of pulmonary carcinoids, suggesting DLL3 and the immune system as candidate therapeutic targets; we confirm the value of OTP expression levels for the prognosis and diagnosis of these diseases, and we unveil the group of supra-carcinoids. This group comprises samples with carcinoid-like morphology yet the molecular and clinical features of the deadly LCNEC, further supporting the previously proposed molecular link between the low- and high-grade lung neuroendocrine neoplasms.

Original languageEnglish
Article number3407
JournalNature Communications
Volume10
Issue number1
DOIs
Publication statusPublished - 20 Aug 2019

Bibliographical note

Acknowledgements
We thank the patients donating their tumour specimens. We also thank Prof. Roman K. Thomas, Dr. Martin Peifer, Dr. Julie George, Dr. Paul Brennan, and Dr. Ghislaine Scelo for their help with logistics. We also thank Dr. Ricard Argelaguet for his advice in using MOFA. This study is part of the lungNENomics project and the Rare Cancers Genomics initiative (www.rarecancersgenomics.com). This work has been funded by the US National Institutes of Health (NIH R03CA195253 to L.F.C. and J.D.M.), the French National Cancer Institute (INCa, PRT-K-17-047 to L.F.C. and TABAC 17-022 to J.D.M.), the Ligue Nationale contre le Cancer (LNCC 2016 to L.F.C.), France Genomique (to J.D.M.), and the Italian Association for Cancer Research (AIRC) (IG 19238 to M.V. and MFAG 12983 to L.A.M.) (Special Programme 5X1000, ED No12162 to U.P., L.R., and G.S.). J.S. is a Miguel Servet researcher (CP13/00055 and PI16/0295). L.M. and T.M.D. have fellowships from the LNCC.

Publisher Copyright: © 2019, The Author(s).

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