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

Our plain-English summary of Multiomic analysis of malignant pleural mesothelioma identifies molecular axes and specialized tumor profiles driving intertumor heterogeneity, by L. Mangiante, N. Alcala, A. Sexton-Oates, et al (Nature Genetics, 2023).

The study

• Authors: L. Mangiante, N. Alcala, A. Sexton-Oates, A. Di Genova, A. Gonzalez-Perez, A. Khandekar, E.N. Bergstrom, J. Kim, X. Liu, R. Blazquez-Encinas, C. Giacobi, N. Le Stang, S. Boyault, C. Cuenin, S. Tabone-Eglinger, F. Damiola, C. Voegele, M. Ardin, M.C. Michallet, L. Soudade, T.M. Delhomme, A. Poret, M. Brevet, M.C. Copin, S. Giusiano-Courcambeck, D. Damotte, C. Girard, V. Hofman, P. Hofman, J. Mouroux, C. Cohen, S. Lacomme, J. Mazieres, V.T. de Montpreville, C. Perrin, G. Planchard, N. Rousseau, I. Rouquette, C. Sagan, A. Scherpereel, F. Thivolet, J.M. Vignaud, D. Jean, A.G.S. Ilg, R. Olaso, V. Meyer, A. Boland-Auge, J.F. Deleuze, J. Altmuller, P. Nuernberg, A. Ibáñez-Costa, J.P. Castaño, S. Lantuejoul, A. Ghantous, C. Maussion, P. Courtiol, H. Hernandez-Vargas, C. Caux, N. Girard, N. Lopez-Bigas, L.B. Alexandrov, F. Galateau-Salle, M. Foll, L. Fernandez-Cuesta
• Journal: Nature Genetics
• Published: 2023;55(4):607-618
• Cited by: 74 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

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).

In plain English

This laboratory study analysed malignant pleural mesothelioma (MPM) tumors from 123 patients in the French MESOBANK. Three patients previously treated with chemotherapy were excluded, leaving 120 tumors. The authors combined whole-genome sequencing with gene-activity (RNA) and DNA methylation data. The standard WHO tissue-type classification accounted for only up to 10% of molecular differences between patients. Four statistical factors (ploidy, tumor cell morphology, adaptive immune response and CpG island methylation) together accounted for up to 61%. Survival was lowest for the greatest ploidy and better for tumors with high immune infiltration. It was also better for CIMP-low than CIMP-high tumors. Of 115 tumors, 111 (97%) carried at least one large genomic event. No single-base substitution signature was associated with asbestos exposure. Expression of mesenchymal genes correlated positively with an asbestos exposure score (r = 0.44). Timing estimates in six tumors, three from asbestos-exposed patients, suggested genomic events can occur during and after asbestos exposure. The authors said this needs testing in hypothesis-driven studies. The authors concluded the work paves the way for a classification combining morphology and molecular features.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Multiomic molecular study of tumor samples: whole-genome sequencing, RNA sequencing and DNA methylation, integrated by multi-omics factor analysis, with survival analysis and replication in published cohorts
• Who was studied: Tumor material from 123 patients with malignant pleural mesothelioma provided by the French MESOBANK. Three patients previously treated with chemotherapy were excluded from most analyses, leaving 120 tumors. Study dates not given in the text.
• Exposure: Asbestos exposure was recorded per patient as exposed or non-exposed, and an asbestos exposure score was used in some analyses. No asbestos fiber types or doses are named in the text.
• Main results:
  • In the 120 tumors, the WHO histopathological classification accounted for up to 10% of interpatient molecular differences.
  • Four latent factors (ploidy, morphology, adaptive immune response, CIMP) collectively explained up to 61% of interpatient differences, depending on the molecular layer.
  • Survival was lowest for tumors with the greatest ploidy.
  • Tumors with high immune infiltration had better survival, and CIMP-low tumors had better survival than CIMP-high tumors.
  • 111 of 115 tumors (97%) had at least one large genomic event.
  • None of the ten single-base substitution signatures detected was associated with asbestos exposure.
  • Expression of mesenchymal genes was positively correlated with the asbestos exposure score.
  • 23% of the samples showed a homologous recombination deficiency (HRD) phenotype.
  • Combining MESOMICS with two published datasets (about 300 samples), the authors identified 30 MPM driver genes from small variants.
  • Timing estimates in six samples, three from asbestos-exposed patients, suggested to the authors that genomic events can occur both during and after asbestos exposure.
  • The authors reported that tumors specialized in cell division and tumor–immune interaction tended to occur in intensely asbestos-exposed individuals.
• The authors' conclusion: The authors concluded that 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.
• Limitations the authors state:
  • When only epithelioid (MME) samples were analysed, the prognostic value of the ploidy and CIMP factors was not statistically significant. The authors attributed this probably to limited power and a possible effect of histology.
  • An E2F-target finding could not be replicated in the TCGA cohort, possibly because of small sample size.
  • Cell-line models lack a microenvironment, so the adaptive response factor could not be replicated in drug-response analyses.
  • Timing of genomic events was estimated in only six samples, and the authors stated that conclusive evidence on timing requires hypothesis-driven studies.

Topics

The National Library of Medicine indexes this study under subjects our site covers: Lung cancer, Mesothelioma.

Medical terms in this study, explained in our Lexicon: Pleural Mesothelioma.

Related studies

• Redefining malignant pleural mesothelioma types as a continuum uncovers immune-vascular interactions — N. Alcala, L. Mangiante, et al. (2019)
• Multi-site tumor sampling highlights molecular intra-tumor heterogeneity in malignant pleural mesothelioma — C. Meiller, F. Montagne, et al. (2021)
• New Insights on Diagnostic Reproducibility of Biphasic Mesotheliomas: A Multi-Institutional Evaluation by the International Mesothelioma Panel From the MESOPATH Reference Center — F. Galateau Salle, N. Le Stang, et al. (2018)
• Genetic alterations of malignant pleural mesothelioma: association with tumor heterogeneity and overall survival — L. Quetel, C. Meiller, et al. (2020)
• Unraveling tumor microenvironment heterogeneity in malignant pleural mesothelioma identifies biologically distinct immune subtypes enabling prognosis determination — K. Yang, T. Yang, et al. (2022)
• A molecular phenotypic map of malignant pleural mesothelioma — A. Di Genova, L. Mangiante, et al. (2022)

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