Molecular Classification of Malignant Pleural Mesothelioma: Identification of a Poor Prognosis Subgroup Linked to the Epithelial-to-Mesenchymal Transition

Abstract

Purpose: 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 clinicobiological heterogeneity. The identification of molecular profiles is a powerful approach to better define MPM subclasses and targeted therapies.Experimental Design: 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. Clin Cancer Res; 20(5); 1323-34. Ó2014 AACR.

BAP1 (BRCA1-associated protein 1) is a highly specific marker for differentiating mesothelioma from reactive mesothelial proliferations

“…Interestingly, in this study mutation analysis of BAP1, CDKN2A, CDKN2B, NF2, and TP53 was also performed and showed that the subgroup with better prognosis exhibited more frequent BAP1 genetic variants. 74 This observation is in keeping with the data obtained by Arzt et al 57 who found that lack of BAP1 protein expression in mesothelioma is associated with better survival.…”

Germline Mutation of Bap1 Accelerates Development of Asbestos-Induced Malignant Mesothelioma

“…In our report of human BAP1 families (11), all of the available malignant mesothelioma specimens seen in BAP1 mutation carriers were of the epithelial type, although the significance of this finding could not be established because of the relatively small number of cases evaluated. In sporadic malignant mesothelioma, several groups have reported that somatic mutations of BAP1 occur primarily in epithelioid tumors (11,12,38), whereas…”

BAP1, a tumor suppressor gene driving malignant mesothelioma

“…Also comparable, was the association of somatically inactivated BAP1 with the epithelioid MM subtype (36). Since BAP1 can influence the regulation of gene expression epigenetically or through deubiquitination of transcription factors (see below), it is plausible that these different patterns of gene expression can lead to variations in MM tumor subtypes (35,40,41).…”