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 González-Pérez, Azhar Khandekar, Erik N. Bergstrom, Jaehee Kim, Xiran Liu, Ricardo Blázquez‐Encinas, Colin Giacobi, Nolwenn Le Stang, Sandrine Boyault, Cyrille Cuenin, Séverine Tabone‐Eglinger, Francesca Damiola, Catherine Voegele, Maude Ardin, Marie‐Cécile Michallet, Lorraine Soudade, Tiffany M. Delhomme, Arnaud Poret, Marie Brevet, Marie‐Christine Copin, Sophie Giusiano, Diane Damotte, Cécile Girard, Véronique Hofman, Paul Hofman, Jérôme Mouroux, Charlotte Cohen, Stéphanie Lacomme, Julien Mazières, Vincent de Montpréville, Corinne Perrin, G. Planchard, Nathalie Rousseau, Isabelle Rouquette, Christine Sagan, Arnaud Scherpereel, F. Thivolet, Jean-Michel Vignaud, Didier Jean, Anabelle Gilg Soit Ilg, Robert Olaso, Vincent Meyer, Anne Boland, Jean‐François Deleuze, Janine Altmüller, Peter Nüernberg, Alejandro Ibáñez‐Costa, Justo P. Castaño, Sylvie Lantuéjoul, Akram Ghantous, Charles Maussion, Pierre Courtiol, Héctor Hernández‐Vargas, Christophe Caux, Nicolas Girard, Núria López-Bigas, Ludmil B. Alexandrov, Françoise Galateau-Sallé, Matthieu Foll, Lynnette Fernandez‐Cuesta
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.