Molecular classification of malignant pleural mesothelioma: identification of a poor prognosis subgroup linked to the epithelial-to-mesenchymal transition.
OBJECTIVE
Despite research efforts to develop more effective diagnostic and therapeutic approaches, malignant pleural mesothelioma (MPM) prognosis remains poor. The assessment of tumor response to therapy can be improved by a deeper phenotypical classification of the tumor, with emphasis on its clinico-biological heterogeneity. The identification of molecular profiles is a powerful approach to better define MPM subclasses and targeted therapies.


METHODS
Molecular subclasses were defined by transcriptomic microarray on 38 primary MPM cultures. A three-gene predictor, identified by quantitative reverse transcription PCR, was used to classify an independent series of 108 frozen tumor samples. Gene mutations were determined in BAP1, CDKN2A, CDKN2B, NF2, and TP53. Epithelial-to-mesenchymal transition (EMT) markers were studied at the mRNA and protein levels.


RESULTS
Unsupervised hierarchical clustering on transcriptomic data defined two robust MPM subgroups (C1 and C2), closely related to prognosis and partly to histologic subtypes. All sarcomatoid/desmoplastic MPM were included in the C2 subgroup. Epithelioid MPM were found in both subgroups, with a worse survival prognosis in the C2 subgroup. This classification and its association with histologic subtypes and survival were validated in our independent series using the three-gene predictor. Similar subgroups were found after classification of other MPM series from transcriptomic public datasets. C1 subgroup exhibited more frequent BAP1 alterations. Pathway analysis revealed that EMT was differentially regulated between MPM subgroups. C2 subgroup is characterized by a mesenchymal phenotype.


CONCLUSIONS
A robust classification of MPM that defines two subgroups of epithelioid MPM, characterized by different molecular profiles, gene alterations, and survival outcomes, was established.
Authors' Affiliations: Ligue Nationale Contre Le Cancer, Programme Cartes d'Identité des Tumeurs (CIT); INSERM, UMR-1162, Génomique fonctionnel des tumeurs solides, IUH; Université Paris Descartes; Université Paris Diderot; Université Paris 13; Labex Immuno-Oncology; Sorbonne Paris Cité; AP-HP, GHU Ouest, Hôpital Européen Georges Pompidou, Laboratoire d'Anatomie Pathologique; AP-HP, GHU Ouest, Hôpital Européen Georges Pompidou, Service de Chirurgie Thoracique, Paris; CHRU Lille, Service de Chirurgie Cardiaque; CHRU Lille, Université de Lille II, Institut de Pathologie, Centre de Biologie-Pathologie, 59037 Lille; CHU Caen, Service d'Anatomo-Pathologie; INSERM, U1086, Caen; CHU Nice, Laboratoire de Pathologie Clinique et Expérimentale (LPCE) et Biobanque Humaine, Hôpital Pasteur, Nice; Centre Hospitalier Intercommunal de Créteil, Service de Pneumologie et de Pathologie Professionnelle; and INSERM, U955, Equipe 4, Créteil, France.
Aurélien
A
de Reyniès
Marie-Claude
MC
Jaurand
Annie
A
Renier
Gabrielle
G
Couchy
Ilir
I
Hysi
Nabila
N
Elarouci
Françoise
F
Galateau-Sallé
Marie-Christine
MC
Copin
Paul
P
Hofman
Aurélie
A
Cazes
Pascal
P
Andujar
Sandrine
S
Imbeaud
Fabien
F
Petel
Jean-Claude
JC
Pairon
Francoise
F
Le Pimpec-Barthes
Jessica
J
Zucman-Rossi
Didier
D
Jean
D000368:Aged; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D016000:Cluster Analysis; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics*; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D008175:Lung Neoplasms / Q000175:diagnosis* / Q000235:genetics* / Q000401:mortality; D008297:Male; D008654:Mesothelioma / Q000175:diagnosis* / Q000235:genetics* / Q000401:mortality; D000086002:Mesothelioma, Malignant; D008875:Middle Aged; D009154:Mutation; D009367:Neoplasm Staging; D010997:Pleural Neoplasms / Q000175:diagnosis* / Q000235:genetics* / Q000401:mortality; D011379:Prognosis; D014407:Tumor Cells, Cultured; D025521:Tumor Suppressor Proteins / Q000235:genetics; D043222:Ubiquitin Thiolesterase / Q000235:genetics
C400134:BAP1 protein, human; D014408:Biomarkers, Tumor; D025521:Tumor Suppressor Proteins; D043222:Ubiquitin Thiolesterase