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

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.

SUBMITTER: Mangiante L

PROVIDER: S-EPMC10101853 | biostudies-literature | 2023 Apr

REPOSITORIES: biostudies-literature

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

Mangiante Lise L Alcala Nicolas N Sexton-Oates Alexandra A Di Genova Alex A Gonzalez-Perez Abel A Khandekar Azhar A Bergstrom Erik N EN Kim Jaehee J Liu Xiran X Blazquez-Encinas Ricardo R Giacobi Colin C Le Stang Nolwenn N Boyault Sandrine S Cuenin Cyrille C Tabone-Eglinger Severine S Damiola Francesca F Voegele Catherine C Ardin Maude M Michallet Marie-Cecile MC Soudade Lorraine L Delhomme Tiffany M TM Poret Arnaud A Brevet Marie M Copin Marie-Christine MC Giusiano-Courcambeck Sophie S Damotte Diane D Girard Cecile C Hofman Veronique V Hofman Paul P Mouroux Jérôme J Cohen Charlotte C Lacomme Stephanie S Mazieres Julien J de Montpreville Vincent Thomas VT Perrin Corinne C Planchard Gaetane G Rousseau Nathalie N Rouquette Isabelle I Sagan Christine C Scherpereel Arnaud A Thivolet Francoise F Vignaud Jean-Michel JM Jean Didier D Ilg Anabelle Gilg Soit AGS Olaso Robert R Meyer Vincent V Boland-Auge Anne A Deleuze Jean-Francois JF Altmuller Janine J Nuernberg Peter P Ibáñez-Costa Alejandro A Castaño Justo P JP Lantuejoul Sylvie S Ghantous Akram A Maussion Charles C Courtiol Pierre P Hernandez-Vargas Hector H Caux Christophe C Girard Nicolas N Lopez-Bigas Nuria N Alexandrov Ludmil B LB Galateau-Salle Françoise F Foll Matthieu M Fernandez-Cuesta Lynnette L

Nature genetics 20230316 4

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 fo ...[more]

PMID: 36928603

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Project description:Malignant pleural mesothelioma (MPM) is a highly lethal, poorly understood neoplasm that is typically associated with asbestos exposure. We performed transcriptional profiling using high-density oligonucleotide microarrays containing approximately 22,000 genes to elucidate potential molecular and pathobiological pathways in MPM using discarded human MPM tumor specimens (n=40), normal lung specimens (n=4), normal pleura specimens (n=5), and MPM and SV40-immortalized mesothelial cell lines (n=5). In global expression analysis using unsupervised clustering techniques, we found two potential subclasses of mesothelioma which correlate loosely with tumor histology. We also identified sets of genes with expression levels that distinguish between multiple tumor subclasses, normal and tumor tissues, and tumors with different morphologies. Microarray gene expression data were confirmed using quantitative reverse transcriptase-polymerase chain reaction (RT-PCR) and protein analysis for three novel candidate oncogenes (NME2, CRI1, and PDGFC) and one candidate tumor suppressor (GSN). Finally, we used bioinformatics tools (i.e. software) to create and explore complex physiological pathways that may be relevant in mesothelioma tumorigenesis, pathobiology, or both. Tissues and cell lines profiled using microarrays. Discarded MPM surgical specimens (n=40), normal pleura specimens (n=5), and normal lung specimens (n=4) were freshly collected (and snap frozen) from patients who underwent surgery at Boston's Brigham and Women's Hospital (BWH) between October 1998 and August 2000. All of these patients underwent extrapleural pneumonectomy with heated intra-pleural cisplatin chemotherapy delivered after the specimens were removed. All normal specimens were obtained from patients who were never diagnosed with MPM. Two human MPM cell lines (MS589 and MS428) were kindly provided by Jonathan A. Fletcher, M.D., Department of Pathology, BWH. The JMN1B MPM cell line19,20 has been described previously. The SV40-immortalized, non-tumorigenic mesothelial cell line (Met-5A)21 and the MPM cell line MSTO-211H22 were purchased from the American Type Culture Collection. Normal tissues were obtained from additional consented patients undergoing treatment for diseases other than MPM. All MPM samples used in these studies contained relatively pure tumor (greater than 50% tumor cells per high power field examined in a section adjacent to the tissue used). The microscopic slides from the patients' resection specimens were reviewed by one of the authors (J.G.), and the diagnosis and histologic subclassification of MPM confirmed in all cases. Linked clinical and pathological data were obtained for all patients who contributed tumor specimens. Specimens and data were rendered anonymous to protect patient confidentiality. Studies utilizing human tissues were approved by and conducted in accordance with the policies of the Institutional Review Board at BWH.

Project description:BackgroundMalignant pleural mesothelioma (MPM) is a heterogeneous cancer. Better knowledge of molecular and cellular intra-tumor heterogeneity throughout the thoracic cavity is required to develop efficient therapies. This study focuses on molecular intra-tumor heterogeneity using the largest series to date in MPM and is the first to report on the multi-omics profiling of a substantial series of multi-site tumor samples.MethodsIntra-tumor heterogeneity was investigated in 16 patients from whom biopsies were taken at distinct anatomical sites. The paired biopsies collected from apex, side wall, costo-diaphragmatic, or highest metabolic sites as well as 5 derived cell lines were screened using targeted sequencing. Whole exome sequencing, RNA sequencing, and DNA methylation were performed on a subset of the cohort for deep characterization. Molecular classification, recently defined histo-molecular gradients, and cell populations of the tumor microenvironment were assessed.ResultsSequencing analysis identified heterogeneous variants notably in NF2, a key tumor suppressor gene of mesothelial carcinogenesis. Subclonal tumor populations were shared among paired biopsies, suggesting a polyclonal dissemination of the tumor. Transcriptome analysis highlighted dysregulation of cell adhesion and extracellular matrix pathways, linked to changes in histo-molecular gradient proportions between anatomic sites. Methylome analysis revealed the contribution of epigenetic mechanisms in two patients. Finally, significant changes in the expression of immune mediators and genes related to immunological synapse, as well as differential infiltration of immune populations in the tumor environment, were observed and led to a switch from a hot to a cold immune profile in three patients.ConclusionsThis comprehensive analysis reveals patient-dependent spatial intra-tumor heterogeneity at the genetic, transcriptomic, and epigenetic levels and in the immune landscape of the tumor microenvironment. Results support the need for multi-sampling for the implementation of molecular-based precision medicine.

Dataset Information

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

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

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