title: Co-occurring Mutations of Tumor Suppressor Genes,LATS2andNF2, in Malignant Pleural Mesothelioma.
abstract: Purpose:To better define malignant pleural mesothelioma (MPM) heterogeneity and identify molecular subtypes of MPM, we focus on the tumor suppressor geneLATS2, 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 inLATS2Gene 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:TheLATS2gene 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 theLATS2andNF2genes in the same MPM. MPM patients of this subgroup presented a poor prognosis. Coinactivation ofLATS2andNF2leads to loss of cell contact inhibition between MPM cells. Hippo signaling pathway activity, mTOR expression, and phosphorylation were altered in the C2LNMPM subgroup. MPMs of this new subgroup show higher sensitivity to PF-04691502 inhibitor. TheMOKgene was identified as a potential biomarker of the C2LNMPM 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.
authors.affiliation: 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.
authors.forename: Robin
authors.initials: R
authors.lastname: Tranchant
authors.affiliation: 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.
authors.forename: Lisa
authors.initials: L
authors.lastname: Quetel
authors.affiliation: Génomique Fonctionnelle des Tumeurs Solides, INSERM, UMR-1162, Equipe labellisée Ligue Contre le Cancer, Paris, France.
authors.forename: Anne
authors.initials: A
authors.lastname: Tallet
authors.affiliation: 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.
authors.forename: Clement
authors.initials: C
authors.lastname: Meiller
authors.affiliation: 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.
authors.forename: Annie
authors.initials: A
authors.lastname: Renier
authors.affiliation: Translational Research Department, Institut Curie, PSL Research University, Paris, France.
authors.forename: Leanne
authors.initials: L
authors.lastname: de Koning
authors.affiliation: Programme Cartes d'Identité des Tumeurs (CIT), Ligue Nationale Contre Le Cancer, Paris, France.
authors.forename: Aurelien
authors.initials: A
authors.lastname: de Reynies
authors.affiliation: 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.|Département de Chirurgie Thoracique, Hopital Européen Georges Pompidou, Paris, France.|Assistance Publique-Hopitaux de Paris, Hopital Européen Georges Pompidou, Paris, France.
authors.forename: Francoise
authors.initials: F
authors.lastname: Le Pimpec-Barthes
authors.affiliation: 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.|Assistance Publique-Hopitaux de Paris, Hopital Européen Georges Pompidou, Paris, France.
authors.forename: Jessica
authors.initials: J
authors.lastname: Zucman-Rossi
authors.affiliation: 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.
authors.forename: Marie-Claude
authors.initials: MC
authors.lastname: Jaurand
authors.affiliation: Génomique Fonctionnelle des Tumeurs Solides, INSERM, UMR-1162, Equipe labellisée Ligue Contre le Cancer, Paris, France. didier.jean@inserm.fr.|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.
authors.forename: Didier
authors.initials: D
authors.lastname: Jean
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D017209:Apoptosis / Q000235:genetics; D049109:Cell Proliferation / Q000235:genetics; D002470:Cell Survival / Q000235:genetics; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D016147:Genes, Tumor Suppressor; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D008297:Male; D008654:Mesothelioma / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D000086002:Mesothelioma, Malignant; D008875:Middle Aged; D009154:Mutation; D009361:Neoplasm Invasiveness / Q000235:genetics / Q000473:pathology; D016518:Neurofibromatosis 2 / Q000235:genetics*; D010997:Pleural Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D011728:Pyridones / Q000008:administration & dosage; D011743:Pyrimidines / Q000008:administration & dosage; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors; D025521:Tumor Suppressor Proteins / Q000235:genetics*
chemical_list: C570662:2-amino-8-(4-(2-hydroxyethoxy)cyclohexyl)-6-(6-methoxypyridin-3-yl)-4-methylpyrido(2,3-d)pyrimidin-7(8H)-one; D011728:Pyridones; D011743:Pyrimidines; D025521:Tumor Suppressor Proteins; C546842:MTOR protein, human; C406449:LATS2 protein, human; D017346:Protein Serine-Threonine Kinases; D058570:TOR Serine-Threonine Kinases