Jerôme Cros1,2,3, Nathalie Théou-Anton4, Valérie Gounant5, Remy Nicolle6, Cécile Reyes7, Sarah Humez8, Ségolène Hescot9, Vincent Thomas de Montpréville10, Serge Guyétant11, Jean-Yves Scoazec12,13, Alice Guyard1, Louis de Mestier2,3,14, Solenn Brosseau2,5, Pierre Mordant2,15, Yves Castier2,15, David Gentien7, Philippe Ruszniewski2,3,14, Gérard Zalcman2,5, Anne Couvelard16,17,18, Aurélie Cazes1,2,19. 1. Department of Pathology, ENETS Centre of Excellence, Beaujon-Bichat Hospitals, AP-HP, Paris, France. 2. Université de Paris, Paris, France. 3. INSERM U1149, Centre de Recherche sur l'Inflammation, Paris, France. 4. Department of Genetics, Bichat Hospital, AP-HP, Paris, France. 5. Department of Thoracic Oncology and Early Phase Clinical Trials Unit (CIC1425/CLIP2), Bichat Hospital, AP-HP, Paris, France. 6. Programme Cartes d'Identité des Tumeurs (CIT), Ligue Nationale Contre le Cancer, Paris, France. 7. Institut Curie, PSL Research University, Translational Research Department, Genomics Platform, Paris, France. 8. Department of Pathology, CHRU de Lille, Lille, France. 9. Department of Nuclear Medicine, Institut Curie, CLCC, Saint-Cloud, France. 10. Department of Pathology, Marie Lannelongue Hospital, Le Plessis Robinson, France. 11. Department of Pathology, CHRU de Tours, Tours, France. 12. Department of Biopathology, Gustave Roussy Cancer Campus, Villejuif, France. 13. Faculté de Médecine, Université Paris Saclay, Le Kremlin-Bicêtre, France. 14. Department of Gastroenterology and Pancreatology, Beaujon Hospital, AP-HP, Clichy, France. 15. Department of Vascular and Thoracic Surgery, Bichat University Hospital, AP-HP, Université de Paris, Paris, France. 16. Department of Pathology, ENETS Centre of Excellence, Beaujon-Bichat Hospitals, AP-HP, Paris, France, anne.couvelard@bch.aphp.fr. 17. Université de Paris, Paris, France, anne.couvelard@bch.aphp.fr. 18. INSERM U1149, Centre de Recherche sur l'Inflammation, Paris, France, anne.couvelard@bch.aphp.fr. 19. INSERM U1152, Paris, France.
Abstract
INTRODUCTION: High-grade lung neuroendocrine tumours with carcinoid morphology have been recently reported; they may represent the thoracic counterparts of grade 3 digestive neuroendocrine tumours. We aimed to study their genetic landscape including analysis of tumoral heterogeneity. METHODS: Eleven patients with high-grade (>20% Ki-67 and/or >10 mitoses) lung neuroendocrine tumours with a carcinoid morphology were included. We analysed copy number variations, somatic mutations, and protein expression in 16 tumour samples (2 samples were available for 5 patients allowing us to study spatial and temporal heterogeneity). RESULTS: Genomic patterns were heterogeneous ranging from "quiet" to tetraploid, heavily rearranged genomes. Oncogene mutations were rare and most genetic alterations targeted tumour suppressor genes. Chromosomes 11 (7/11), 3 (6/11), 13 (4/11), and 6-17 (3/11) were the most frequently lost. Altered tumour suppressor genes were common to both carcinoids and neuroendocrine carcinomas, involving different pathways including chromatin remodelling (KMT2A, ARID1A, SETD2, SMARCA2, BAP1, PBRM1, KAT6A), DNA repair (MEN1, POLQ, ATR, MLH1, ATM), cell cycle (RB1, TP53, CDKN2A), cell adhesion (LATS2, CTNNB1, GSK3B) and metabolism (VHL). Comparative spatial/temporal analyses confirmed that these tumours emerged from clones of lower aggressivity but revealed that they were genetically heterogeneous accumulating "neuroendocrine carcinoma-like" genetic alterations through progression such as TP53/RB1 alterations. CONCLUSION: These data confirm the importance of chromatin remodelling genes in pulmonary carcinoids and highlight the potential role of TP53 and RB1 to drive the transformation in more aggressive high-grade tumours.
INTRODUCTION: High-grade lung neuroendocrine tumours with carcinoid morphology have been recently reported; they may represent the thoracic counterparts of grade 3 digestive neuroendocrine tumours. We aimed to study their genetic landscape including analysis of tumoral heterogeneity. METHODS: Eleven patients with high-grade (>20% Ki-67 and/or >10 mitoses) lung neuroendocrine tumours with a carcinoid morphology were included. We analysed copy number variations, somatic mutations, and protein expression in 16 tumour samples (2 samples were available for 5 patients allowing us to study spatial and temporal heterogeneity). RESULTS: Genomic patterns were heterogeneous ranging from "quiet" to tetraploid, heavily rearranged genomes. Oncogene mutations were rare and most genetic alterations targeted tumour suppressor genes. Chromosomes 11 (7/11), 3 (6/11), 13 (4/11), and 6-17 (3/11) were the most frequently lost. Altered tumour suppressor genes were common to both carcinoids and neuroendocrine carcinomas, involving different pathways including chromatin remodelling (KMT2A, ARID1A, SETD2, SMARCA2, BAP1, PBRM1, KAT6A), DNA repair (MEN1, POLQ, ATR, MLH1, ATM), cell cycle (RB1, TP53, CDKN2A), cell adhesion (LATS2, CTNNB1, GSK3B) and metabolism (VHL). Comparative spatial/temporal analyses confirmed that these tumours emerged from clones of lower aggressivity but revealed that they were genetically heterogeneous accumulating "neuroendocrine carcinoma-like" genetic alterations through progression such as TP53/RB1 alterations. CONCLUSION: These data confirm the importance of chromatin remodelling genes in pulmonary carcinoids and highlight the potential role of TP53 and RB1 to drive the transformation in more aggressive high-grade tumours.
Authors: Marco Volante; Ozgur Mete; Giuseppe Pelosi; Anja C Roden; Ernst Jan M Speel; Silvia Uccella Journal: Endocr Pathol Date: 2021-02-27 Impact factor: 3.943