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

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

Journal: Nature genetics 2023;55(4):607-618

PMID: 36928603

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.

© 2023. The Author(s).

Address: Rare Cancers Genomics Team, Genomic Epidemiology Branch, International Agency for Research on Cancer/World Health Organization, Lyon, France.; Department of Medicine, Stanford University, Stanford, CA, USA.; Rare Cancers Genomics Team, Genomic Epidemiology Branch, International Agency for Research on Cancer/World Health Organization, Lyon, France.; Rare Cancers Genomics Team, Genomic Epidemiology Branch, International Agency for Research on Cancer/World Health Organization, Lyon, France.; Instituto de Ciencias de la Ingeniería, Universidad de O'Higgins, Rancagua, Chile.; Centro de Modelamiento Matemático UMI-CNRS 2807, Universidad de Chile, Santiago, Chile.; Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Barcelona, Spain.; Centro de Investigación Biomédica en Red en Cáncer, Instituto de Salud Carlos III, Madrid, Spain.; Department of Cellular and Molecular Medicine, Department of Bioengineering and Moores Cancer Center, University of California, San Diego, La Jolla, CA, USA.; Institute for Computational and Mathematical Engineering, Stanford University, Stanford, CA, USA.; Department of Computational Biology, Cornell University, Ithaca, NY, USA.; Institute for Computational and Mathematical Engineering, Stanford University, Stanford, CA, USA.; Maimonides Biomedical Research Institute of Cordoba, Córdoba, Spain.; Department of Cell Biology, Physiology and Immunology, University of Cordoba, Córdoba, Spain.; Reina Sofia University Hospital, Córdoba, Spain.; CIBER Fisiopatología de la Obesidad y Nutrición, Córdoba, Spain.; UMR INSERM 1052, CNRS 5286, Cancer Research Center of Lyon, MESOPATH-MESOBANK, Department of Biopathology, Cancer Centre Léon Bérard, Lyon, France.; Cancer Genomic Platform, Translational Research and Innovation Department, Centre Léon Bérard, Lyon, France.; EpiGenomics and Mechanisms Branch, International Agency for Research on Cancer/World Health Organization, Lyon, France.; Tumor Escape, Resistance and Immunity Department, Centre de Recherche en Cancérologie de Lyon, Centre Léon Bérard, Université de Lyon, Université Claude Bernard Lyon 1, INSERM 1052, CNRS 5286, Lyon, France.; Rare Cancers Genomics Team, Genomic Epidemiology Branch, International Agency for Research on Cancer/World Health Organization, Lyon, France.; Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Barcelona, Spain.; Cypath and Cypath-rb, Villeurbanne, France.; University of Lille, Centre Hospitalier Universitaire Lille, Institut de Pathologie, Tumorothèque du Centre de Référence Régional en Cancérologie, Lille, France.; Department of Pathology, Centre Hospitalier Universitaire Nord, Marseille, France.; Centre de Recherche des Cordeliers, Inflammation, Complement and Cancer Team, Sorbonne Université, INSERM, Université de Paris, Paris, France.; Department of Pathology, Hôpitaux Universitaire Paris Centre, Tumorothèque/CRB Cancer, Cochin Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France.; Tumorothèque Centre Hospitalier Universitaire de Nantes, Nantes, France.; Université Côte d'Azur, Laboratory of Clinical and Experimental Pathology, Nice Center Hospital, FHU OncoAge, Biobank BB-0033-00025 and IRCAN Inserm U1081/CNRS 7284, Nice, France.; Université Côte d'Azur, Department of Thoracic Surgery, Nice Center Hospital, FHU OncoAge and IRCAN Inserm U1081/CNRS 7284, Nice, France.; Department of Thoracic Surgery, FHU OncoAge, Nice Pasteur Hospital, Université Côte d'Azur, Nice, France.; Nancy Regional University Hospital, Centre Hospitalier Régional Universitaire, CRB BB-0033-00035, INSERM U1256, Nancy, France.; Toulouse University Hospital, Université Paul Sabatier, Toulouse, France.; Department of Pathology, Marie Lannelongue Hospital, Le Plessis Robinson, France.; Hospices Civils de Lyon, Institut de Pathologie, Centre de Ressources Biologiques des HCL, Tissu-Tumorothèque Est, Lyon, France.; Centre Hospitalier Universitaire de Caen, MESOPATH Regional Center, Caen, France.; Centre de Pathologie des Côteaux, Centre de Ressources Biologiques (CRB Cancer), IUCT Oncopole, Toulouse, France.; University of Lille, Centre Hospitalier Universitaire Lille, INSERM, OncoThAI, NETMESO Network, Lille, France.; Department of Biopathology, Centre Hospitalier Régional Universitaire de Nancy, Vandoeuvre-les-Nancy, France.; BRC, BB-0033-00035, Centre Hospitalier Régional Universitaire de Nancy, Vandoeuvre-les-Nancy, France.; Centre de Recherche des Cordeliers, INSERM, Sorbonne Université, Université de Paris, Functional Genomics of Solid Tumors, Paris, France.; Direction Santé Environnement Travail, Santé Publique France, Paris, France.; Université Paris-Saclay, CEA, Centre National de Recherche en Génomique Humaine, Evry, France.; Cologne Centre for Genomics, Cologne, Germany.; UMR INSERM 1052, CNRS 5286, Cancer Research Center of Lyon, MESOPATH-MESOBANK, Department of Biopathology, Cancer Centre Léon Bérard, Lyon, France.; Grenoble Alpes University, Saint-Martin-d'Hères, France.; Owkin, New York, NY, USA.; UMR INSERM 1052, CNRS 5286, UCBL1, Centre Léon Bérard, Lyon, France.; Centre de Recherche en Cancérologie de Lyon, Lyon, France.; Institut Curie, Institut du Thorax Curie Montsouris, Paris, France.; Université de Versailles Saint-Quentin-en-Yvelines, Université Paris-Saclay, Versailles, France.; Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Barcelona, Spain.; Centro de Investigación Biomédica en Red en Cáncer, Instituto de Salud Carlos III, Madrid, Spain.; Institució Catalana de Recerca i Estudis Avançats, Barcelona, Spain.; Rare Cancers Genomics Team, Genomic Epidemiology Branch, International Agency for Research on Cancer/World Health Organization, Lyon, France. [email protected].; Rare Cancers Genomics Team, Genomic Epidemiology Branch, International Agency for Research on Cancer/World Health Organization, Lyon, France. [email protected].
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