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1. Multiomic analysis of malignant pleural mesothelioma identifies molecular axes and specialized tumor profiles driving intertumor heterogeneity

Author

Lise Mangiante, Nicolas Alcala, Alexandra Sexton-Oates, Alex Di Genova, Abel Gonzalez-Perez, Azhar Khandekar, Erik N. Bergstrom, Jaehee Kim, Xiran Liu, Ricardo Blazquez-Encinas, Colin Giacobi, Nolwenn Le Stang, Sandrine Boyault, Cyrille Cuenin, Severine Tabone-Eglinger, Francesca Damiola, Catherine Voegele, Maude Ardin, Marie-Cecile Michallet, Lorraine Soudade, Tiffany M. Delhomme, Arnaud Poret, Marie Brevet, Marie-Christine Copin, Sophie Giusiano-Courcambeck, Diane Damotte, Cecile Girard, Veronique Hofman, Paul Hofman, Jérôme Mouroux, Charlotte Cohen, Stephanie Lacomme, Julien Mazieres, Vincent Thomas de Montpreville, Corinne Perrin, Gaetane Planchard, Nathalie Rousseau, Isabelle Rouquette, Christine Sagan, Arnaud Scherpereel, Francoise Thivolet, Jean-Michel Vignaud, Didier Jean, Anabelle Gilg Soit Ilg, Robert Olaso, Vincent Meyer, Anne Boland-Auge, Jean-Francois Deleuze, Janine Altmuller, Peter Nuernberg, Alejandro Ibáñez-Costa, Justo P. Castaño, Sylvie Lantuejoul, Akram Ghantous, Charles Maussion, Pierre Courtiol, Hector Hernandez-Vargas, Christophe Caux, Nicolas Girard, Nuria Lopez-Bigas, Ludmil B. Alexandrov, Françoise Galateau-Salle, Matthieu Foll, Lynnette Fernandez-Cuesta, Centre International de Recherche contre le Cancer - International Agency for Research on Cancer (CIRC - IARC), Organisation Mondiale de la Santé / World Health Organization Office (OMS / WHO), Stanford University, Universidad de O'Higgins (UOH), Centre de modélisation mathématique (CMM), Universitad de Chile-Centre National de la Recherche Scientifique (CNRS), Barcelona Institute of Science and Technology (BIST), Instituto de Salud Carlos III [Madrid] (ISC), University of California [San Diego] (UC San Diego), University of California (UC), Cornell University [New York], Maimonides Institute of Biomedical Research of Cordoba, Partenaires INRAE, Universidad de Córdoba = University of Córdoba [Córdoba], Hospital Universitario Reina Sofia [Cordoue, Espagne], CIBER Fisiopatología de la Obesidad y Nutrición [Cordoue, Espagne] (CIBEROBN), Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre Léon Bérard [Lyon], Cypath and Cypath-rb [Villeurbanne] (2C), Tumorothèque du Centre de Référence Régional en Cancérologie [CHRU Lille] (T-C2RC), Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Institut de Pathologie de Lille (IPL), Hôpital Nord [CHU - APHM], Centre de Recherche des Cordeliers (CRC (UMR_S_1138 / U1138)), École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université Paris Cité (UPCité), Tumorothèque - Centre de Ressources Biologiques Cancer Cochin [Hôpital Cochin AP-HP] (T-CRB Cancer Cochin), Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Groupes hospitalo-universitaires Paris Centre AP-HP [Paris] (GHU Paris Centre), FHU OncoAge - Pathologies liées à l’âge [CHU Nice] (OncoAge), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut de Pharmacologie Moléculaire et Cellulaire [UNIV Côte d'Azur] (UPMC)-Université Côte d'Azur (UCA), Université Côte d'Azur (UCA), Institut de Recherche sur le Cancer et le Vieillissement (IRCAN), Université Nice Sophia Antipolis (1965 - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA), Centre Hospitalier Universitaire de Nice (CHU Nice), Hôpital Pasteur [Nice] (CHU), Nutrition-Génétique et Exposition aux Risques Environnementaux (NGERE), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Hôpital Marie-Lannelongue, Tissu-Tumorothèque Est - Centre de Ressources Biologiques [HCL, Lyon] (2TE - CRB HCL), Hospices Civils de Lyon (HCL), Réseau d'expertise anatomopathologique et de recherche sur les tumeurs de la plèvre [CHU Caen] (MESOPATH), CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN), Service Anatomie et cytologie pathologiques [CHU Toulouse], Pôle Biologie [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Centre de Ressources Biologiques - Cancer - IUCT Oncopole [Toulouse] (CRB - Cancer Toulouse), Thérapies Laser Assistées par l'Image pour l'Oncologie - U 1189 (ONCO-THAI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Santé publique France - French National Public Health Agency [Saint-Maurice, France], Centre National de Recherche en Génomique Humaine (CNRGH), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Cologne Centre for Genomics [Cologne, Germany] (2CG), Instituto Maimonides de Investigación Biomédica de Cordoba (IMIBIC), Universidad de Córdoba = University of Córdoba [Córdoba]-Hospital Universitario Reina Sofía, Université Grenoble Alpes (UGA), Owkin [New York, NY, USA] (O), Institut Curie [Paris], Institut Mutualiste de Montsouris (IMM), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), Université Paris-Saclay, and Institució Catalana de Recerca i Estudis Avançats (ICREA)

Subjects
[SDV]Life Sciences [q-bio], Genetics, Technology Platforms
Abstract

Malignant pleural mesothelioma (MPM) is an aggressive cancer with rising incidence and challenging clinical management. Through a large series of whole-genome sequencing data, integrated with transcriptomic and epigenomic data using multiomics factor analysis, we demonstrate that the current World Health Organization classification only accounts for up to 10% of interpatient molecular differences. Instead, the MESOMICS project paves the way for a morphomolecular classification of MPM based on four dimensions: ploidy, tumor cell morphology, adaptive immune response and CpG island methylator profile. We show that these four dimensions are complementary, capture major interpatient molecular differences and are delimited by extreme phenotypes that—in the case of the interdependent tumor cell morphology and adapted immune response—reflect tumor specialization. These findings unearth the interplay between MPM functional biology and its genomic history, and provide insights into the variations observed in the clinical behavior of patients with MPM.

Published
2023
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2. Hepatitis B virus preS2Δ38–55 variants: A newly identified risk factor for hepatocellular carcinoma

Author

Fabien Zoulim, Pierre Simon Garcia, Valentin Tilloy, Saunab Ghosh, Yusuke Shimakawa, Maud Lemoine, Janet Hall, Céline Brochier-Armanet, Njie Ramou, Anaëlle Dubois, Nora Kakwata-Nkor Deluce, Damien Cohen, Clément Guillot, Sophie Alain, Geoffroy Durand, Isabelle Chemin, Maimuna Mendy, Mark Thursz, Florence Le Calvez-Kelm, Umberto D'Alessandro, Catherine Voegele, Gibril Ndow, Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Epidémiologie des Maladies Emergentes - Emerging Diseases Epidemiology, Pasteur-Cnam Risques infectieux et émergents (PACRI), Institut Pasteur [Paris] (IP)-Conservatoire National des Arts et Métiers [CNAM] (CNAM), HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-Institut Pasteur [Paris] (IP)-Conservatoire National des Arts et Métiers [CNAM] (CNAM), HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM), Centre International de Recherche contre le Cancer - International Agency for Research on Cancer (CIRC - IARC), Organisation Mondiale de la Santé / World Health Organization Office (OMS / WHO), Laboratoire de Biométrie et Biologie Evolutive - UMR 5558 (LBBE), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS), Hôpital Dupuytren [CHU Limoges], London School of Hygiene and Tropical Medicine [Fajara, Gambia], London School of Hygiene and Tropical Medicine (LSHTM), Hospices Civils de Lyon (HCL), Imperial College London, European Commission (FP7), Agence Nationale de Recherches sur le Sida et les Hepatites Virales (12357), the ARC Santé from the Region Auvergne Rhône-Alpes, NIHR Imperial Biomedical Research Centre., Imperial College Healthcare NHS Trust: Research Capability Funding (RCF), Medical Research Council (MRC), Institut Pasteur [Paris]-Conservatoire National des Arts et Métiers [CNAM] (CNAM), HESAM Université (HESAM)-HESAM Université (HESAM)-Institut Pasteur [Paris]-Conservatoire National des Arts et Métiers [CNAM] (CNAM), and HESAM Université (HESAM)-HESAM Université (HESAM)

Subjects
WT, wild type, HBsAg, Aflatoxin B1, Carcinogenesis, Hepatocellular carcinoma, NBS1, Nijmegen breakage syndrome 1, LSM, liver stiffness measurement, medicine.disease_cause, [SDV.BID.SPT]Life Sciences [q-bio]/Biodiversity/Systematics, Phylogenetics and taxonomy, Liver disease, 0302 clinical medicine, PreS deletion, Genotype, INFECTION, Immunology and Allergy, LIVER-CANCER, SSA, sub-Saharan Africa, ComputingMilieux_MISCELLANEOUS, 2. Zero hunger, 0303 health sciences, education.field_of_study, AFP, alpha-fetoprotein, [SDV.BID.EVO]Life Sciences [q-bio]/Biodiversity/Populations and Evolution [q-bio.PE], Gastroenterology, GAMBIA, CARRIERS, [SDV.BIBS]Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], 3. Good health, Cirrhosis, 030211 gastroenterology & hepatology, Liver cancer, Viral load, Life Sciences & Biomedicine, AFB1, aflatoxin B1, Research Article, Hepatitis B virus, PROTEINS, Population, ER, endoplasmic reticulum, 03 medical and health sciences, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Internal Medicine, medicine, lcsh:RC799-869, education, 030304 developmental biology, Science & Technology, Hepatology, Gastroenterology & Hepatology, business.industry, DNA, medicine.disease, GENOTYPES, Virology, [SDV.MP.BAC]Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology, GENE, PROLIFICA, Prevention of Liver Fibrosis and Cancer in Africa, digestive system diseases, SUBGENOTYPE, ROC, receiver operating characteristic, DELETIONS, NGS, next-generation sequencing, OR, odds ratio, Africa, lcsh:Diseases of the digestive system. Gastroenterology, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, business
Abstract

Background & Aims Although HBV is a major cause of death in Africa, its genetic variability has been poorly documented. This study aimed to address whether HBV genotype and surface gene variants are associated with HBV-related liver disease in The Gambia. Methods We conducted a case-control study nested in the Prevention of Liver Fibrosis and Cancer in Africa programme. Consecutive treatment-naive patients with chronic HBV infection and detectable viral load were recruited: 211 controls with no significant liver disease and 91 cases (56 cirrhosis and 35 HCC cases). HBV genotypes and surface gene variants were determined by Sanger sequencing or next-generation sequencing (NGS) in serum DNA. Aflatoxin B1 (AFB1)-specific codon 249 TP53 mutation was determined by NGS in circulating cell-free plasma DNA. Results In phylogenetic analysis, 85% of individuals carried HBV genotype E, 14% genotype A, and 1% A/E recombinant viruses. Surface gene variants were more frequently observed in cases (43% and 57% in cirrhosis and HCC cases, respectively) than controls (25%; p 2,000 IU/ml (OR 22.7 [8.0–64.9]), HBsAg levels, Graphical abstract, Highlights • The rarer HBV genotype A (vs. E) is associated with a higher risk of HCC (odds ratio 5.2). • A genotype-independent deletion hotspot was found in the preS2 domain (preS2Δ38–55). • PreS2Δ38–55 was significantly associated with HCC and is an independent risk factor.

Published
2020
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3. Integrative and comparative genomic analyses identify clinically relevant pulmonary carcinoid groups and unveil the supra-carcinoids

Author

F. Le Calvez-Kelm, John K. Field, Nicolas Girard, Ernst-Jan M. Speel, Marie Brevet, Lynnette Fernandez-Cuesta, Jean-François Deleuze, Nicolas Lemaitre, Noémie Leblay, Sandrine Boyault, Marius Lund-Iversen, Gabriella Sozzi, Véronique Hofman, Sylvie Lantuejoul, Lucia Anna Muscarella, Paolo Graziano, Alex Soltermann, Matthieu Foll, Amelie Chabrier, Robert Olaso, A. Ferrari, Anne Boland, Paul Hofman, Luca Roz, Behnoush Abedi-Ardekani, Janine Altmüller, Tiffany M. Delhomme, Akram Ghantous, Christophe Caux, Jules L. Derks, Giuseppe Pelosi, Vincent Meyer, Anne-Marie C. Dingemans, Juan Sandoval, Jean-Michel Vignaud, Jelena Stojsic, Catherine Voegele, Geoffroy Durand, James D. McKay, Peter Nuernberg, Cyrille Cuenin, Nicolas Alcala, L. Moonen, Hector Hernandez-Vargas, Ugo Pastorino, Theo Giffon, O.T. Brustugun, L. Mangiante, Mauro Papotti, Philippe Lorimier, Anne-Claire Toffart, Prudence A. Russell, Aurélie A G Gabriel, Zdenko Herceg, A. S. Sertier, Joachim H. Clement, M. Milione, Joerg Saenger, Luka Brcic, Stéphanie Lacomme, V. Thomas de Montpreville, A. Viari, Marco Volante, Elisabeth Brambilla, Gavin M. Wright, Cécile Blanc-Fournier, David Hervás, N. Le Stang, H. Popper, Françoise Galateau-Sallé, Centre international de Recherche sur le Cancer (CIRC), Hospital Universitari i Politècnic La Fe = University and Polytechnic Hospital La Fe, Fondation Synergie Lyon Cancer [Lyon], Centre Léon Bérard [Lyon], Maastricht University Medical Centre (MUMC), Maastricht University [Maastricht], Institut de Biologie François JACOB (JACOB), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Cologne Center for Genomics [Cologne] (CCG), University of Cologne, Centre for Molecular Medicine Cologne [Cologne] (CMMC), University Hospital of Cologne [Cologne], School for Oncology and Developmental Biology [Maastricht] (GROW), Maastricht University [Maastricht]-Maastricht University Medical Centre (MUMC), Institute for Advanced Biosciences / Institut pour l'Avancée des Biosciences (Grenoble) (IAB), Centre Hospitalier Universitaire [Grenoble] (CHU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang - Auvergne-Rhône-Alpes (EFS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Service de pneumologie [Grenoble], Centre Hospitalier Universitaire [Grenoble] (CHU), Institute of Pathology and Molecular Pathology [Zurich], Department Hematology and Medical Oncology [Jena], Jena University Hospital [Jena], Central Clinic Bad Berka, Department of Molecular and Clinical Cancer Medicine [Liverpool], University of Liverpool, Université Claude Bernard Lyon 1 (UCBL), Université de Lyon, Centre Régional de Lutte contre le Cancer François Baclesse [Caen] (UNICANCER/CRLC), Normandie Université (NU)-UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN), University of Melbourne, IRCCS Istituto Nazionale dei Tumori [Milano], Nutrition-Génétique et Exposition aux Risques Environnementaux (NGERE), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), Institut de Recherche sur le Cancer et le Vieillissement (IRCAN), Université Nice Sophia Antipolis (1965 - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA), Oslo University Hospital [Oslo], Centre Chirurgical Marie Lannelongue (CCML), Istituto di Ricovero e Cura a Carattere Scientifico, Ospedale Casa Sollievo della Sofferenza [San Giovanni Rotondo] (IRCCS), University Hospital Graz, Clinical Center of Serbia (KCS), Equipe de recherche européenne en algorithmique et biologie formelle et expérimentale (ERABLE), Inria Grenoble - Rhône-Alpes, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria), Università degli Studi di Milano = University of Milan (UNIMI), Università degli studi di Torino = University of Turin (UNITO), Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Hospital Universitari i Politècnic La Fe, Synergie Lyon Cancer [Lyon], UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU), Université Nice Sophia Antipolis (... - 2019) (UNS), Centre chirurgical Marie Lannelongue, University of Milan, University of Turin, RS: GROW - R3 - Innovative Cancer Diagnostics & Therapy, Promovendi ODB, Pulmonologie, RS: GROW - R2 - Basic and Translational Cancer Biology, MUMC+: MA Med Staf Spec Longziekten (9), and Pathologie

Subjects
0301 basic medicine, Oncology, Male, Lung Neoplasms, [SDV]Life Sciences [q-bio], General Physics and Astronomy, Datasets as Topic, 02 engineering and technology, Neuroendocrine tumors, Machine Learning, PATHWAY, Cancer genomics, lcsh:Science, Lung, Aged, 80 and over, Comparative Genomic Hybridization, Multidisciplinary, Intracellular Signaling Peptides and Proteins, Genomics, Middle Aged, 021001 nanoscience & nanotechnology, Prognosis, 3. Good health, Neuroendocrine Carcinomas, Survival Rate, medicine.anatomical_structure, Female, Non small cell, HEALTH, Technology Platforms, 0210 nano-technology, Adult, EXPRESSION, medicine.medical_specialty, Adolescent, Science, CELL LUNG-CANCER, Nerve Tissue Proteins, Carcinoid Tumor, DENDRITIC CELLS, General Biochemistry, Genetics and Molecular Biology, Article, Small-cell lung cancer, CLASSIFICATION, 03 medical and health sciences, Young Adult, Internal medicine, Overall survival, medicine, Carcinoma, Biomarkers, Tumor, Humans, Survival rate, Aged, Homeodomain Proteins, IDENTIFICATION, business.industry, MUTATIONS, Membrane Proteins, General Chemistry, medicine.disease, Small Cell Lung Carcinoma, 030104 developmental biology, DISCOVERY, Carcinoma, Large Cell, lcsh:Q, business, NEUROENDOCRINE TUMORS, Comparative genomic hybridization
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., The worldwide incidence of pulmonary carcinoids is increasing, but little is known about their molecular characteristics. Here, Alcala and colleagues present a multi-omics analysis of these tumours, revealing distinct molecular and prognostic subgroups.

Published
2019
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