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

Lise Mangiante (1, 2) , Nicolas Alcala (1) , Alexandra Sexton-Oates (1) , Alex Di Genova (1, 3, 4) , Abel Gonzalez-Perez (5, 6) , Azhar Khandekar (7) , Erik Bergstrom (7) , Jaehee Kim (2, 8) , Xiran Liu (2) , Ricardo Blazquez-Encinas (9, 10, 11, 12) , Colin Giacobi (1) , Nolwenn Le Stang (13, 14) , Sandrine Boyault (14) , Cyrille Cuenin (1) , Severine Tabone-Eglinger (13, 14) , Francesca Damiola (13, 14) , Catherine Voegele (1) , Maude Ardin (13) , Marie-Cécile Michallet (13) , Lorraine Soudade (1) , Tiffany Delhomme (1) , Arnaud Poret (1) , Marie Brevet (15) , Marie-Christine Copin (16) , Sophie Giusiano-Courcambeck (17) , Diane Damotte (18) , Cecile Girard (19) , Veronique Hofman (20, 21, 22, 23) , Paul Hofman (20, 21, 22, 23) , Jérôme Mouroux (20, 21, 22, 23) , Charlotte Cohen (20, 24) , Stephanie Lacomme (25, 26) , Julien Mazieres (27, 28) , Vincent Thomas de Montpreville (29) , Corinne Perrin (30) , Gaetane Planchard (31) , Nathalie Rousseau (31) , Isabelle Rouquette (32, 33) , Christine Sagan (34) , Arnaud Scherpereel (35) , Francoise Thivolet (30) , Jean-Michel Vignaud (26) , Didier Jean (18) , Anabelle Gilg Soit Ilg (36) , Robert Olaso (37) , Vincent Meyer (37) , Anne Boland-Auge (37) , Jean-Francois Deleuze (37) , Janine Altmuller (38) , Peter Nuernberg (38) , Alejandro Ibáñez-Costa (10, 9, 39, 12) , Justo Castaño (10, 9, 39, 12) , Sylvie Lantuejoul (13, 40, 41) , Akram Ghantous (1) , Charles Maussion (42) , Pierre Courtiol (42) , Hector Hernandez-Vargas (13) , Christophe Caux (13) , Nicolas Girard (43, 44, 45, 46) , Nuria Lopez-Bigas (5, 6, 47) , Ludmil Alexandrov (7) , Françoise Galateau-Salle (13) , Matthieu Foll (1) , Lynnette Fernandez-Cuesta (1)

1 CIRC - IARC - Centre International de Recherche contre le Cancer - International Agency for Research on Cancer
2 Stanford University
3 UOH - Universidad de O'Higgins
4 CMM - Centre de modélisation mathématique / Centro de Modelamiento Matemático [Santiago]
5 BIST - Barcelona Institute of Science and Technology
6 ISC - Instituto de Salud Carlos III [Madrid]
7 UC San Diego - University of California [San Diego]
8 Cornell University [New York]
9 Universidad de Córdoba = University of Córdoba [Córdoba]
10 IMIBIC - Instituto Maimonides de Investigación Biomédica de Cordoba
11 Hospital Universitario Reina Sofía de Córdoba
12 CIBEROBN - CIBER Fisiopatología de la Obesidad y Nutrición [Cordoue, Espagne]
13 UNICANCER/CRCL - Centre de Recherche en Cancérologie de Lyon
14 Centre Léon Bérard [Lyon]
15 2C - Cypath and Cypath-rb [Villeurbanne]
16 T-C2RC - Tumorothèque du Centre de Référence Régional en Cancérologie [CHRU Lille]
17 Hôpital Nord [CHU - APHM]
18 CRC (UMR_S_1138 / U1138) - Centre de Recherche des Cordeliers
19 CHU Nantes - Centre Hospitalier Universitaire de Nantes = Nantes University Hospital
20 OncoAge - FHU OncoAge - Pathologies liées à l’âge [CHU Nice]
21 UniCA - Université Côte d'Azur
22 IRCAN - Institut de Recherche sur le Cancer et le Vieillissement
23 CHU Nice - Centre Hospitalier Universitaire de Nice
24 CHU - Hôpital Pasteur [Nice]
25 NGERE - Nutrition-Génétique et Exposition aux Risques Environnementaux
26 CRB Nancy - Centre de Ressources Biologiques - [Nancy]
27 UT3 - Université Toulouse III - Paul Sabatier
28 CHU Toulouse - Centre Hospitalier Universitaire de Toulouse
29 Hôpital Marie-Lannelongue
30 2TE - CRB HCL - Tissu-Tumorothèque Est - Centre de Ressources Biologiques [HCL, Lyon]
31 MESOPATH - Réseau d'expertise anatomopathologique et de recherche sur les tumeurs de la plèvre [CHU Caen]
32 Service Anatomie et cytologie pathologiques [CHU Toulouse]
33 CRB - Cancer Toulouse - Centre de Ressources Biologiques - Cancer - IUCT Oncopole [Toulouse]
34 T-CRB Cancer Cochin - Tumorothèque - Centre de Ressources Biologiques Cancer Cochin [Hôpital Cochin AP-HP]
35 OncoThAI - Thérapies Assistées par Lasers et Immunothérapies pour l'Oncologie - U 1189
36 Santé publique France - French National Public Health Agency [Saint-Maurice, France]
37 CNRGH - Centre National de Recherche en Génomique Humaine
38 CCG - Cologne Center for Genomics [Cologne]
39 Hospital Universitario Reina Sofia [Cordoue, Espagne]
40 UGA - Université Grenoble Alpes
41 Plateforme anatomopathologie recherche Lyon-Est
42 Owkin, Inc. [New York, NY, États-Unis]
43 Institut Curie [Paris]
44 IMM - Institut Mutualiste de Montsouris
45 UVSQ - Université de Versailles Saint-Quentin-en-Yvelines
46 Université Paris-Saclay
47 ICREA - Institució Catalana de Recerca i Estudis Avançats = Catalan Institution for Research and Advanced Studies

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.

Domaines: Sciences du Vivant [q-bio]

Lise Mangiante, Nicolas Alcala, Alexandra Sexton-Oates, Alex Di Genova, Abel Gonzalez-Perez, et al.. Multiomic analysis of malignant pleural mesothelioma identifies molecular axes and specialized tumor profiles driving intertumor heterogeneity. Nature Genetics, 2023, 55 (4), pp.607-618. ⟨10.1038/s41588-023-01321-1⟩. ⟨inserm-04062865⟩