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Clin Cancer Res. 2017 Jun 15;23(12):3191-3202. doi: 10.1158/1078-0432.CCR-16-1971. Epub 2016 Dec 21.

Co-occurring Mutations of Tumor Suppressor Genes, LATS2 and NF2, in Malignant Pleural Mesothelioma.

Tranchant R1,2,3,4, Quetel L1,2,3,4, Tallet A1, Meiller C1,2,3,4, Renier A1,2,3,4, de Koning L5, de Reynies A6, Le Pimpec-Barthes F1,2,3,4,7,8, Zucman-Rossi J1,2,3,4,8, Jaurand MC1,2,3,4, Jean D9,2,3,4.

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Génomique Fonctionnelle des Tumeurs Solides, INSERM, UMR-1162, Equipe labellisée Ligue Contre le Cancer, Paris, France.
Université Paris Descartes, Sorbonne Paris Cité, Labex Immuno-oncology, Paris, France.
Institut Universitaire d'Hématologie, Université Paris Diderot, Sorbonne Paris Cité, Paris, France.
Université Paris 13, Sorbonne Paris Cité, Saint-Denis, France.
Translational Research Department, Institut Curie, PSL Research University, Paris, France.
Programme Cartes d'Identité des Tumeurs (CIT), Ligue Nationale Contre Le Cancer, Paris, France.
Département de Chirurgie Thoracique, Hopital Européen Georges Pompidou, Paris, France.
Assistance Publique-Hopitaux de Paris, Hopital Européen Georges Pompidou, Paris, France.
Génomique Fonctionnelle des Tumeurs Solides, INSERM, UMR-1162, Equipe labellisée Ligue Contre le Cancer, Paris, France.


Purpose: To better define malignant pleural mesothelioma (MPM) heterogeneity and identify molecular subtypes of MPM, we focus on the tumor suppressor gene LATS2, a member of the Hippo signaling pathway, which plays a key role in mesothelial carcinogenesis.Experimental Design: Sixty-one MPM primary cultures established in our laboratory were screened for mutations in LATS2 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.Results: The LATS2 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, C2LN, characterized by a co-occurring mutation in the LATS2 and NF2 genes in the same MPM. MPM patients of this subgroup presented a poor prognosis. Coinactivation of LATS2 and NF2 leads to loss of cell contact inhibition between MPM cells. Hippo signaling pathway activity, mTOR expression, and phosphorylation were altered in the C2LN MPM subgroup. MPMs of this new subgroup show higher sensitivity to PF-04691502 inhibitor. The MOK gene was identified as a potential biomarker of the C2LN MPM subgroup and PF-04691502 sensitivity.Conclusions: 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. Clin Cancer Res; 23(12); 3191-202. ©2016 AACR.

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