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; H. Meyer; J. Altmuller; F. Le Calvez-Kelm; G. Durand; C. 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; M. 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

doi:10.1038/s41467-019-11276-9

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, H. 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, M. 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

Research output: Contribution to journal › Article › Academic › peer-review

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 language	English
Article number	3407
Pages (from-to)	1-21
Number of pages	21
Journal	Nature Communications
Volume	10
Issue number	1
DOIs	https://doi.org/10.1038/s41467-019-11276-9
Publication status	Published - 20 Aug 2019

Keywords

CELL LUNG-CANCER
NEUROENDOCRINE TUMORS
DENDRITIC CELLS
EXPRESSION
CLASSIFICATION
MUTATIONS
DISCOVERY
PATHWAY
HEALTH
IDENTIFICATION

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Alcala, N., Leblay, N., Gabriel, A. A. G., Mangiante, L., Hervas, D., Giffon, T., Sertier, A. S., Ferrari, A., Derks, J., Ghantous, A., Delhomme, T. M., Chabrier, A., Cuenin, C., Abedi-Ardekani, B., Boland, A., Olaso, R., Meyer, H., Altmuller, J., Le Calvez-Kelm, F., ... Fernandez-Cuesta, L. (2019). Integrative and comparative genomic analyses identify clinically relevant pulmonary carcinoid groups and unveil the supra-carcinoids. Nature Communications, 10(1), 1-21. Article 3407. https://doi.org/10.1038/s41467-019-11276-9

@article{8b325f3565c242cd9a03f8287be588f7,

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

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.",

keywords = "CELL LUNG-CANCER, NEUROENDOCRINE TUMORS, DENDRITIC CELLS, EXPRESSION, CLASSIFICATION, MUTATIONS, DISCOVERY, PATHWAY, HEALTH, IDENTIFICATION",

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

note = "Funding Information: 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: {\textcopyright} 2019, The Author(s).",

year = "2019",

month = aug,

day = "20",

doi = "10.1038/s41467-019-11276-9",

language = "English",

volume = "10",

pages = "1--21",

journal = "Nature Communications",

issn = "2041-1723",

publisher = "Nature Publishing Group",

number = "1",

}

Alcala, N, Leblay, N, Gabriel, AAG, Mangiante, L, Hervas, D, Giffon, T, Sertier, AS, Ferrari, A, Derks, J, Ghantous, A, Delhomme, TM, Chabrier, A, Cuenin, C, Abedi-Ardekani, B, Boland, A, Olaso, R, Meyer, H, Altmuller, J, Le Calvez-Kelm, F, Durand, G, Voegele, C, Boyault, S, Moonen, L, Lemaitre, N, Lorimier, P, Toffart, AC, Soltermann, A, Clement, JH, Saenger, J, Field, JK, Brevet, M, Blanc-Fournier, C, Galateau-Salle, F, Le Stang, N, Russell, PA, Wright, G, Sozzi, G, Pastorino, U, Lacomme, S, Vignaud, JM, Hofman, M, Hofman, P, Brustugun, OT, Lund-Iversen, M, de Montpreville, VT, Muscarella, LA, Graziano, P, Popper, H, Stojsic, J, Deleuze, JF, Herceg, Z, Viari, A, Nuernberg, P, Pelosi, G, Dingemans, AMC, Milione, M, Roz, L, Brcic, L, Volante, M, Papotti, MG, Caux, C, Sandoval, J, Hernandez-Vargas, H, Brambilla, E, Speel, EJM, Girard, N, Lantuejoul, S, McKay, JD, Foll, M & Fernandez-Cuesta, L 2019, 'Integrative and comparative genomic analyses identify clinically relevant pulmonary carcinoid groups and unveil the supra-carcinoids', Nature Communications, vol. 10, no. 1, 3407, pp. 1-21. https://doi.org/10.1038/s41467-019-11276-9

TY - JOUR

T1 - Integrative and comparative genomic analyses identify clinically relevant pulmonary carcinoid groups and unveil the supra-carcinoids

AU - Alcala, N.

AU - Leblay, N.

AU - Gabriel, A. A. G.

AU - Mangiante, L.

AU - Hervas, D.

AU - Giffon, T.

AU - Sertier, A. S.

AU - Ferrari, A.

AU - Derks, J.

AU - Ghantous, A.

AU - Delhomme, T. M.

AU - Chabrier, A.

AU - Cuenin, C.

AU - Abedi-Ardekani, B.

AU - Boland, A.

AU - Olaso, R.

AU - Meyer, H.

AU - Altmuller, J.

AU - Le Calvez-Kelm, F.

AU - Durand, G.

AU - Voegele, C.

AU - Boyault, S.

AU - Moonen, L.

AU - Lemaitre, N.

AU - Lorimier, P.

AU - Toffart, A. C.

AU - Soltermann, A.

AU - Clement, J. H.

AU - Saenger, J.

AU - Field, J. K.

AU - Brevet, M.

AU - Blanc-Fournier, C.

AU - Galateau-Salle, F.

AU - Le Stang, N.

AU - Russell, P. A.

AU - Wright, G.

AU - Sozzi, G.

AU - Pastorino, U.

AU - Lacomme, S.

AU - Vignaud, J. M.

AU - Hofman, M.

AU - Hofman, P.

AU - Brustugun, O. T.

AU - Lund-Iversen, M.

AU - de Montpreville, V. Thomas

AU - Muscarella, L. A.

AU - Graziano, P.

AU - Popper, H.

AU - Stojsic, J.

AU - Deleuze, J. F.

AU - Herceg, Z.

AU - Viari, A.

AU - Nuernberg, P.

AU - Pelosi, G.

AU - Dingemans, A. M. C.

AU - Milione, M.

AU - Roz, L.

AU - Brcic, L.

AU - Volante, M.

AU - Papotti, M. G.

AU - Caux, C.

AU - Sandoval, J.

AU - Hernandez-Vargas, H.

AU - Brambilla, E.

AU - Speel, E. J. M.

AU - Girard, N.

AU - Lantuejoul, S.

AU - McKay, J. D.

AU - Foll, M.

AU - Fernandez-Cuesta, L.

N1 - Funding Information: 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).

PY - 2019/8/20

Y1 - 2019/8/20

N2 - 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.

AB - 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.

KW - CELL LUNG-CANCER

KW - NEUROENDOCRINE TUMORS

KW - DENDRITIC CELLS

KW - EXPRESSION

KW - CLASSIFICATION

KW - MUTATIONS

KW - DISCOVERY

KW - PATHWAY

KW - HEALTH

KW - IDENTIFICATION

U2 - 10.1038/s41467-019-11276-9

DO - 10.1038/s41467-019-11276-9

M3 - Article

C2 - 31431620

SN - 2041-1723

VL - 10

SP - 1

EP - 21

JO - Nature Communications

JF - Nature Communications

IS - 1

M1 - 3407

ER -

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

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Keywords

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