Molecular and immunologic breakthroughs are transforming the management of thoracic cancer, although advances have not been as marked for malignant pleural mesothelioma where pathologic diagnosis has been essentially limited to three histologic subtypes. In order to go towards a more multidisciplinary approach for the histologic classification of MPM, we participated in a multidisciplinary group (pathologists, molecular biologists, surgeons, radiologists, and oncologists), sponsored by EURACAN/IASLC to critically review the current classification and issue recommendations. These multidisciplinary recommendations for pathology classification and application will allow more informative pathologic reporting and potential risk stratification, to support clinical practice, research investigation and clinical trials.
While generating the multi-omic data for our own series of MPMs, we started by reanalysing the publicly available data (Bueno et al. Nat Genet. 2016; TCGA Cancer Discov. 2019) with no assumption of discreteness, i.e., without assuming the existence of groups, which is the way the other studies analysed the data. This idea came from the fact that already at the histological level a continuum is suggested, with biphasic MPMs having from 10 to 90% or epithelioid and sarcomatoid components. For this, we undertook unsupervised analyses of RNA-sequencing data of 284 MPMs, and we identified a continuum of molecular profiles that explained the prognosis of the disease better than any discrete model. The immune and vascular pathways were the major sources of molecular variation, with strong differences in the expression of immune checkpoints and pro-angiogenic genes; the extrema of this continuum had specific molecular profiles: a “hot” bad-prognosis profile, with high lymphocyte infiltration and high expression of immune checkpoints and pro-angiogenic genes; a “cold” bad-prognosis profile, with low lymphocyte infiltration and high expression of pro-angiogenic genes; and a “VEGFR2+/VISTA+” better-prognosis profile, with high expression of immune checkpoint VISTA and pro-angiogenic gene VEGFR2 (Figure below). We validated the gene expression levels at the protein level for a subset of five selected genes belonging to the immune and vascular pathways, in a subset of 103 samples and replicated the molecular profiles as well as their prognostic value in the replication series of 77 additional independent samples.
Characteristics of the three MPM transcriptomic profiles. The schematic position of samples harbouring a given profile in the two-dimensional summary (n=284) is represented in the bottom right panel. For each profile, the hallmarks of cancer generally upregulated are indicated by pictograms in the upper left part, the histological type composition is represented by a pie chart in the upper right part, the proportion of tumour infiltrating lymphocytes estimated from the RNA-seq data is represented by a bar plot in the bottom left part, and the expression of representative genes is represented by a radar plot in the bottom right part. Tissue MicroArray IHC staining from the technical validation series, with 0.6 mm core diameter at 5.2× magnification, for the five-gene panel, are presented above each panel.
We are currently performing a full molecular characterization of malignant pleural mesothelioma types and subtypes through a multi-omic integrative analysis (WGS, RNA-seq, and 850k methylation arrays) of 126 primary tumors. The molecular data will be correlated with morphological (based on Artificial Intelligence), epidemiological, and clinical features. We are also assessing the intra-tumor molecular heterogeneity of malignant pleural mesothelioma through a multi-omic integrative analysis (WGS, RNA-seq, and 850k methylation arrays) of different tumoral regions in a series of 13 mesothelioma patients.
Whole-genome sequencing and multi-omic integrative analyses reveal novel axes of molecular variation and specialized tumor profiles in Malignant Pleural Mesothelioma. Mangiante L, Alcala N, Di Genova A, Sexton-Oates A, Gonzalez-Perez A, Khandekar A, Bergstrom EN, Kim J, Liu X, Giacobi C, Le Stang N, Boyault S, Cuenin C, Tabone-Eglinger S, Damiola F, Voegele C, Ardin M, Michallet M-C, Soudade L, Delhomme TM, Poret A, Brevet M, Copin M-C, Giusiano-Courcambeck S, Damotte D, Girard C, Hofman V, Hofman P, Mouroux J, Lacomme S, Mazieres J, Thomas de Montpreville V, Perrin C, Planchard G, Rousseau N, Rouquette I, Sagan C, Scherpereel A, Thivolet F, Vignaud J-M, Jean D, Gilg Soit Ilg A, Olaso R, Meyer V, Boland A, Deleuze J-F, Altmuller J, Nuernberg P, Lantuejoul S, Ghantous A, Maussion C, Courtiol P, Hernandez-Vargas H, Caux C, Girard N, Lopez-Bigas N, Alexandrov LB, Galateau-Salle F, Foll M, Fernandez-Cuesta L. bioRxiv 2021 (Under 2nd round of revision in Nat Genet.)
Challenges in lung and thoracic pathology: molecular advances in the classification of pleural mesotheliomas. Fernandez-Cuesta L, Mangiante L, Alcala N, Foll M. Virchows Arch. 2021 PMID: 33411030 Review.
Comprehensive molecular and pathological evaluation of transitional mesothelioma assisted by deep learning approach: a multi-institutional study of the International Mesothelioma Panel from MESOPATH Référence Center. Galateau Salle F, Le Stang N, Tirode F, Courtiol P, Nicholson AG, Tsao MS, Tazelaar HD, Churg A, Dacic S, Roggli V, Pissaloux D, Maussion C, Moarii M, Beasley MB, Begueret H, Chapel DB, Copin MC, Gibbs AR, Klebe S, Lantuejoul S, Nabeshima K, Vignaud JM, Attanoos R, Brcic L, Capron F, Chirieac LR, Damiola F, Sequeiros R, Cazes A, Damotte D, Foulet A, Giusiano-Courcambeck S, Hiroshima K, Hofman V, Husain AN, Kerr K, Marchevsky A, Paindavoine S, Picquenot JM, Rouquette I, Sagan C, Sauter J, Thivolet F, Brevet M, Rouvier P, Travis WD, Planchard G, Weynand B, Clozel T, Wainrib G, Fernandez-Cuesta L, Pairon JC, Rusch V, Girard N. J Thorac Oncol. 2020 PMID: 32165206
Redefining malignant pleural mesothelioma types as a continuum uncovers immune-vascular interactions. Alcala N, Mangiante L, Le-Stang N, Gustafon CE, Boyault S, Damiola F, Alcala K, Brevet M, Thivolet-Bejui F, Blanc-Fournier C, Le Rochais JP, Planchard G, Rousseau N, Damotte D, Pairon JC, Copin MC, Scherpereel A, Wasielewski E, Wicquart L, Lacomme S, Vignaud JM, Ancelin G, Girard C, Sagan C, Bonnetaud C, Hofman V, Hofman P, Mouroux J, Thomas de Montpreville V, Clermont-Taranchon E, Mazieres J, Rouquette I, Begueret H, Blay JY, Lantuejoul S, Bueno R, Caux C, Girard N, McKay JD, Foll M, Galateau-Salle F, Fernandez-Cuesta L. EBioMedicine 2019 PMID: 31648983. EBioMedicine editorial. IARC Press release
EURACAN/IASLC proposals for updating the histologic classification of pleural mesothelioma: towards a more multidisciplinary approach. Nicholson AG, Sauter JL, Nowak AK, Kindler HL, Gill RR, Remy-Jardin M, Armato SG, Fernandez-Cuesta L, Bueno R, Alcala N, Foll M, Pass H, Attanoos R, Baas P, Beasley MB, Brcic L, Butnor KJ, Chirieac LR, Churg A, Courtiol P, Dacic S, De Perrot M, Frauenfelder T, Gibbs A, Hirsch FR, Hiroshima K, Husain A, Klebe S, Lantuejoul S, Moreira A, Opitz I, Perol M, Roden A, Roggli V, Scherpereel A, Tirode F, Tazelaar H, Travis WD, Tsao MS, van Schil P, Vignaud JM, Weynand B, Cree I, Rusch VW, Girard N, Galateau-Salle F. J Thorac Oncol. 2019 PMID: 31546041
Highlights of the 14th international mesothelioma interest group meeting: Pathologic separation of benign from malignant mesothelial proliferations and histologic/molecular analysis of malignant mesothelioma subtypes. Churg A, Nabeshima K, Ali G, Bruno R, Fernandez-Cuesta L, Galateau-Salle F. Lung Cancer 2018 PMID: 30268487
BAP1 Is Altered by Copy Number Loss, Mutation, and/or Loss of Protein Expression in More Than 70% of Malignant Peritoneal Mesotheliomas. Leblay N, Leprêtre F, Le Stang N, Gautier-Stein A, Villeneuve L, Isaac S, Maillet D, Galateau-Sallé F, Villenet C, Sebda S, Goracci A, Byrnes G, McKay JD, Figeac M, Glehen O, Gilly FN, Foll M, Fernandez-Cuesta L, Brevet M. J Thorac Oncol. 2017 PMID: 28034829
Since 2016, Lynnette Fernandez-Cuesta and Matthieu Foll are members of the French MESOBANK Scientific Council
Members of the Rare Cancers Genomics Team at IARC have given oral talks about the MESOMICS project in the following international renown meetings:
Intra-tumour heterogeneity of pleural mesothelioma at the single cell level. Department of Defence (DoD, USA). Coordinators. Active.
Transcriptomic characterization of biphasic and sarcomatoid malignant pleural mesotheliomas. La Ligue Contre le Cancer (LNCC, France). Appel d’offres 2020. Coordinators. Active.
Unveiling the intra-tumour heterogeneity of malignant mesothelioma. La Ligue Contre le Cancer (LNCC, France). Appel d'offres 2017. Coordinators. Completed.
Molecular characterisation of malignant pleural mesothelioma. Institut National Du Cancer (INCa, France). PRT-K16-039. Coordinators. Completed.