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

• Published in: Nature genetics Vol. 55; no. 4; pp. 607 - 618
• Main Authors: Mangiante, Lise, Alcala, Nicolas, Sexton-Oates, Alexandra, Di Genova, Alex, Gonzalez-Perez, Abel, Khandekar, Azhar, Bergstrom, Erik N, Kim, Jaehee, Liu, Xiran, Blazquez-Encinas, Ricardo, Giacobi, Colin, Le Stang, Nolwenn, Boyault, Sandrine, Cuenin, Cyrille, Tabone-Eglinger, Severine, Damiola, Francesca, Voegele, Catherine, Ardin, Maude, Michallet, Marie-Cecile, Soudade, Lorraine, Delhomme, Tiffany M, Poret, Arnaud, Brevet, Marie, Copin, Marie-Christine, Giusiano-Courcambeck, Sophie, Damotte, Diane, Girard, Cecile, Hofman, Veronique, Hofman, Paul, Mouroux, Jérôme, Cohen, Charlotte, Lacomme, Stephanie, Mazieres, Julien, de Montpreville, Vincent Thomas, Perrin, Corinne, Planchard, Gaetane, Rousseau, Nathalie, Rouquette, Isabelle, Sagan, Christine, Scherpereel, Arnaud, Thivolet, Francoise, Vignaud, Jean-Michel, Jean, Didier, Ilg, Anabelle Gilg Soit, Olaso, Robert, Meyer, Vincent, Boland-Auge, Anne, Deleuze, Jean-Francois, Altmuller, Janine, Nuernberg, Peter, Ibáñez-Costa, Alejandro, Castaño, Justo P, Lantuejoul, Sylvie, Ghantous, Akram, Maussion, Charles, Courtiol, Pierre, Hernandez-Vargas, Hector, Caux, Christophe, Girard, Nicolas, Lopez-Bigas, Nuria, Alexandrov, Ludmil B, Galateau-Salle, Françoise, Foll, Matthieu, Fernandez-Cuesta, Lynnette
• Format: Journal Article
• Language: English
• Published: United States Nature Publishing Group 01.04.2023; Nature Publishing Group US
• Subjects: Adaptive immunity; Biomarkers, Tumor - genetics; Cancer; Cell morphology; Classification; CpG islands; Cytology; Factor analysis; Gene sequencing; Genomes; Genotype & phenotype; Heterogeneity; Humans; Immune response; Immune system; Life Sciences; Lung Neoplasms - pathology; Medical prognosis; Mesothelioma; Mesothelioma - genetics; Mesothelioma - pathology; Mesothelioma, Malignant - complications; Mesothelioma, Malignant - genetics; Morphology; Multiomics; Mutation; Phenotypes; Pleural Neoplasms - genetics; Pleural Neoplasms - pathology; Ploidy; Proxies; Transcriptomics; Tumors; Whole genome sequencing
• ISSN: 1061-4036; 1546-1718
• DOI: 10.1038/s41588-023-01321-1

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.