lungNENomics - Rare Cancers Genomics

It is widely accepted that lung neuroendocrine tumours (NETs) and lung neuroendocrine carcinomas (NECs) are different diseases and not simply a continuum of neoplasms with a common pathogenesis. However, over the past years it has been suggested that in both the lung and the thymus the progression or transition from NET to NEC, possibly through the accumulation of genetic anomalies, might be possible. In line with this hypothesis and through multi-omics factor analysis of 116 pulmonary carcinoids (including 35 atypical), 75 large-cell neuroendocrine carcinomas (LCNEC), and 66 small-cell lung cancers, we have identified a group of atypical carcinoids that we have named “supra-carcinoids” with carcinoid-like morphology yet the molecular and clinical features of the deadly LCNEC, suggesting that the molecular link between lung NETs and NECs might be subtler than initially thought (Figure below). In the same study we identified clinically relevant molecular groups of pulmonary carcinoids (Alcala et al., Nat Commun 2019).

Multi-omics factor analysis (MOFA) of transcriptomes and methylomes of LNEN samples (typical carcinoids, atypical carcinoids, and LCNEC). Point colours correspond to the histopathological types; coloured circles correspond to predictions of histopathological types by a machine learning (ML) algorithm (random forest classifier); filled coloured shapes represent the three molecular clusters identified by consensus clustering. The density of clinical variables that are significantly associated with a latent factor (ANOVA q-value < 0.05) are represented by kernel density plots next to each axis: histopathological type for latent factor 1, sex and histopathological type for latent factor 2.

Another important contribution that we would like to highlight is the generation of a molecular map of lung neuroendocrine neoplasms (Figure below) (https://tumormap.ucsc.edu/?p=RCG_lungNENomics/LNEN), which provides an interactive way to explore the molecular data and allows easy statistical interrogation, including generating new hypotheses, but also projecting data from studies including fewer samples, (so frequent when working with rare cancers) in order to draw meaningful conclusions (Gabriel et al. Gigascience 2020).

Two-dimensional projection of LNEN transcriptome data using UMAP. The representation was obtained from the TumorMap portal, using the hexagonal grid view, each hexagonal point representing a LNEN sample. Point colours correspond to the molecular clusters defined in the previous publications.

We are currently performing a full molecular characterization of atypical carcinoids and supra-carcinoids (an aggressive group of pulmonary carcinoids that we have recently identified) through a multi-omic integrative analysis (WGS, RNA-seq, and 850k methylation arrays) of 100 primary tumors. The molecular data will be correlated with morphological, epidemiological, and clinical features. Finally, together with T Dayton (in Clever’s lab) we are trying to depict the mechanisms of a possible progression from low to high-aggressive lung neuroendocrine neoplasms by modeling tumor initiation and progression, using state-of-the-art organoid in vitro models.

PUBLICATIONS

A molecular map of lung neuroendocrine neoplasms. Gabriel AAG, Mathian E, Mangiante L, Voegele C, Cahais V, Ghantous A, McKay JD, Alcala N, Fernandez-Cuesta L, Foll M. Gigascience 2020. PMID: 33124659. Accessing and reviewing Controlled Access Data of Rare Cancers. Q&A with Matthieu Foll

New molecular classification of large cell neuroendocrine carcinoma and small cell lung carcinoma with potential therapeutic impacts. Lantuejoul S, Fernandez-Cuesta L, Damiola F, Girard N, McLeer A. Transl Lung Cancer Res. 2020

Impact clinique des études moléculaires des tumeurs neuroendocrines pulmonaires. Foll M, Fernandez-Cuesta L. Correspondances en Onco-Thoracique 2020

Molecular studies of lung neuroendocrine neoplasms uncover new concepts and entities. Fernandez-Cuesta L, Foll M. Transl Lung Cancer Res. 2019 PMID: 32038931

Integrative and comparative genomic analyses identify clinically relevant pulmonary carcinoid groups and unveil the supra-carcinoids. 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 V, 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 V, Hofman P, Brustugun OT, Lund-Iversen M, Thomas de Montpreville V, 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. Nat Commun. 2019 PMID: 31431620. IARC Press Release

A common classification framework for neuroendocrine neoplasms: an International Agency for Research on Cancer (IARC) and World Health Organization (WHO) expert consensus proposal. Rindi G, Klimstra DS, Abedi-Ardekani B, Asa SL, Bosman FT, Brambilla E, Busam KJ, de Krijger RR, Dietel M, El-Naggar AK, Fernandez-Cuesta L, Klöppel G, McCluggage WG, Moch H, Ohgaki H, Rakha EA, Reed NS, Rous BA, Sasano H, Scarpa A, Scoazec JY, Travis WD, Tallini G, Trouillas J, van Krieken JH, Cree IA. Mod Pathol. 2018 PMID: 30140036

Integrative genomic profiling of large-cell neuroendocrine carcinomas reveals distinct subtypes of high-grade neuroendocrine lung tumors. 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. Nat Commun. 2018 PMID: 29535388

New insights into the molecular characteristics of pulmonary carcinoids and large cell neuroendocrine carcinomas, and the impact on their clinical management. Derks JL, Leblay N, Lantuejoul S, Dingemans AC, Speel EM, Fernandez-Cuesta L. J Thorac Oncol. 2018 Review. Erratum in: J Thorac Oncol. 2018 Aug;13(8):1229. PMID: 29454048

Molecular subtypes of pulmonary large-cell neuroendocrine carcinoma predict chemotherapy treatment outcome. Derks JL, Leblay N, Thunnissen E, van Suylen RJ, den Bakker M, Groen HJM, Smit EF, Damhuis R, van den Broek EC, Charbrier A, Foll M, McKay JD, Fernandez-Cuesta L, Speel EM, Dingemans AC; PALGA-Group. Clin Cancer Res. 2018 PMID: 29066508

Frequent mutations in chromatin-remodelling genes in pulmonary carcinoids. Fernandez-Cuesta L, Peifer M, Lu X, Sun R, Ozretić L, Seidal 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 OT, Helland Å, Solberg S, Lund-Iversen M, Ansén S, Stoelben E, Wright GM, Russell P, Wainer Z, Solomon B, Field JK, Hyde R, Davies MP, Heukamp LC, Petersen I, Perner S, Lovly C, Cappuzzo F, Travis WD, Wolf J, Vingron M, Brambilla E, Haas SA, Buettner R, Thomas RK. Nat Commun. 2014 PMID: 24670920

Integrative genome analyses identify key somatic driver mutations of small-cell lung cancer. Peifer M, Fernández-Cuesta L, Sos ML, George J, Seidel D, Kasper LH, Plenker D, Leenders F, Sun R, Zander T, Menon R, Koker M, Dahmen I, Müller C, Di Cerbo V, Schildhaus HU, Altmüller J, Baessmann I, Becker C, de Wilde B, Vandesompele J, Böhm D, Ansén S, Gabler F, Wilkening I, Heynck S, Heuckmann JM, Lu X, Carter SL, Cibulskis K, Banerji S, Getz G, Park KS, Rauh D, Grütter C, Fischer M, Pasqualucci L, Wright G, Wainer Z, Russell P, Petersen I, Chen Y, Stoelben E, Ludwig C, Schnabel P, Hoffmann H, Muley T, Brockmann M, Engel-Riedel W, Muscarella LA, Fazio VM, Groen H, Timens W, Sietsma H, Thunnissen E, Smit E, Heideman DA, Snijders PJ, Cappuzzo F, Ligorio C, Damiani S, Field J, Solberg S, Brustugun OT, Lund-Iversen M, Sänger J, Clement JH, Soltermann A, Moch H, Weder W, Solomon B, Soria JC, Validire P, Besse B, Brambilla E, Brambilla C, Lantuejoul S, Lorimier P, Schneider PM, Hallek M, Pao W, Meyerson M, Sage J, Shendure J, Schneider R, Büttner R, Wolf J, Nürnberg P, Perner S, Heukamp LC, Brindle PK, Haas S, Thomas RK. Nat Genet. 2012 PMID: 22941188

OTHER SCIENTIFIC ORAL COMMUNICATIONS

Lynnette Fernandez-Cuesta will give an oral presentation entitled: « Comprehensive molecular characterisation of lung supra-carcinoids » in the 2020 NETRF Virtual Research Symposium – November 19-20, 2020

Nicolas Alcala gave an oral presentation entitled « A multi-disciplinary multi-omics study of spatial and temporal tumor evolution in thoracic cancers with clinical implications » in the 2019 Gilles Thomas’ Symposium – October 2-4, 2019 in Lyons (France)

Nicolas Alcala gave an oral presentation entitled « New insights from lung NEN molecular data: new entities or new concepts » in the 31st European Congress of Pathology – September 7-11, 2019 in Nice (France)

Lynnette Fernandez-Cuesta gave an oral presentation entitled « Integrative and comparative genomic analyses identify clinically-relevant groups of pulmonary carcinoids and unveil the existence of supra-carcinoids » in XV International Symposium GETNE 2019 – September 19–20, 2019 in Oviedo (Spain)

Matthieu Foll gave an oral presentation entitled « A multidisciplinary multi-omics study of spatial and temporal tumor evolution in thoracic cancers with clinical implications » in the World Conference on Lung Cancer – September 7–10, 2019 in Barcelona (Spain)

Lynnette Fernandez-Cuesta gave an oral presentation entitled « Machine learning and integrative multi-omics analysis identify novel molecular groups of lung neuroendocrine tumors » in the World Conference on Lung Cancer – September 7–10, 2019 in Barcelona (Spain)

Lynnette Fernandez-Cuesta gave an oral presentation entitled « Integrative and comparative genomic analyses identify clinically relevant groups of pulmonary carcinoids and unveil the existence of supra-carcinoids » in the 16th Annual ENETS Conference – March 6-8, 2018 in Barcelona (Spain)

Lynnette Fernandez-Cuesta gave an oral presentation entitled « New insights in molecular pathology of neuroendocrine lung tumours » in the 11th Joint Meeting of the British Division of the IAP and the Pathological Society, together with the NVvP, The Dutch Pathological Society – June 19-22, 2018 in Maastricht (The Netherlands)

FUNDING

Unveiling the evolutionary processes and molecular pathways underlying the development and progression of lung neuroendocrine neoplasms. Worldwide Cancer Research (WCR, UK). 2020 Grant Round. Coordinators. Active

Population genetics of cancer evolution. France-Stanford Center for Interdisciplinary Studies (US). 2020-2021 Collaborative Research Project Grant. Active

Comprehensive molecular characterisation of lung supra-carcinoids. Neuroendocrine Tumor Research Foundation (NETRF, US). 2019 Investigator Award. Coordinators. Active

Genomic characterisation of broncho-pulmonary carcinoids. Institut National Du Cancer (INCa, France). PRT-K17-047. Coordinators. Active

The Orthopedia Homeobox transcription factor (OTP) in the diagnostics and tumorigenesis of lung carcinoids. KWF Kankerbestrijding (DCS, The Netherlands). Collaborators. Active

Epigenomic characterisation of lung neuroendocrine tumours. Ligue Contre le Cancer (LNCC, France). Coordinators. Completed

Genomic and transcriptomic characterisation of atypical carcinoids of the lung. National Institutes of Health (NIH, US). R03 CA195253-01. Coordinators. Completed