Co-occurring Mutations of Tumor Suppressor Genes, and , in Malignant Pleural Mesothelioma.

To better define malignant pleural mesothelioma (MPM) heterogeneity and identify molecular subtypes of MPM, we focus on the tumor suppressor gene , a member of the Hippo signaling pathway, which plays a key role in mesothelial carcinogenesis. Sixty-one MPM primary cultures established in our laboratory were screened for mutations in Gene inactivation was modeled using siRNAs. Gene and protein expressions were analyzed by quantitative RT-PCR, Western blot analysis, and reverse phase protein array. Cell proliferation, viability, apoptosis, mobility, and invasion were determined after siRNA knockdown or YAP (verteporfin), mTOR (rapamycin), and mTOR/PI3K/AKT (PF-04691502) inhibitor treatment. The gene was altered in 11% of MPM by point mutations and large exon deletions. Genetic data coupled with transcriptomic data allowed the identification of a new MPM molecular subgroup, C2, characterized by a co-occurring mutation in the and genes in the same MPM. MPM patients of this subgroup presented a poor prognosis. Coinactivation of and leads to loss of cell contact inhibition between MPM cells. Hippo signaling pathway activity, mTOR expression, and phosphorylation were altered in the C2 MPM subgroup. MPMs of this new subgroup show higher sensitivity to PF-04691502 inhibitor. The gene was identified as a potential biomarker of the C2 MPM subgroup and PF-04691502 sensitivity. We identified a new MPM molecular subgroup that shares common genetic and transcriptomic characteristics. Our results made it possible to highlight a greater sensitivity to an anticancer compound for this MPM subgroup and to identify a specific potential biomarker. .