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

Autor: Françoise Le Pimpec-Barthes, Marie-Claude Jaurand, Jessica Zucman-Rossi, Leanne De Koning, Anne Tallet, Lisa Quetel, Clément Meiller, Aurélien de Reyniès, Annie Renier, Robin Tranchant, Didier Jean
Přispěvatelé: Génomique Fonctionnelle des Tumeurs Solides (U1162), Université Paris 13 (UP13)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Labex Immuno-oncology, Centre de Recherche des Cordeliers (CRC), Université Pierre et Marie Curie - Paris 6 (UPMC)-École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-PRES Sorbonne Paris Cité-Faculté de Médecine, Université Paris 13 (UP13), Institut Universitaire d'Hématologie (IUH), Université Paris Diderot - Paris 7 (UPD7), Laboratoire des biomarqueurs tumoraux circulants [Institut Curie, Paris] (SiRIC - Département de recherche translationnelle), Institut Curie [Paris]-Université Paris sciences et lettres (PSL), Programme CIT, Ligue Nationale Contre le Cancer (LNCC), Service de Chirurgie Thoracique (Hôpital Européen Georges Pompidou [APHP] HEGP), Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), This work was supported by INSERM, the Fondation ARC pour la recherche sur le cancer, the Ligue Contre le Cancer (Ile de France and Oise committees), the Groupement des Entreprises Françaises dans la Lutte contre le Cancer (GEFLUC), and the Chancellerie des Universités de Paris (Legs POIX)., Jean, Didier, Université Pierre et Marie Curie - Paris 6 (UPMC)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-École pratique des hautes études (EPHE), Ligue Nationale Contre le Cancer
Jazyk: angličtina
Rok vydání: 2017
Předmět:
0301 basic medicine
Cancer Research
medicine.disease_cause
[SDV.BBM.BM] Life Sciences [q-bio]/Biochemistry
Molecular Biology/Molecular biology
Exon
0302 clinical medicine
MESH: Aged
80 and over
MESH: Neurofibromatosis 2
MESH: Aged
Mutation
MESH: Middle Aged
Reverse phase protein lysate microarray
MESH: Gene Expression Regulation
Neoplastic
3. Good health
Oncology
MESH: Cell Survival
030220 oncology & carcinogenesis
[SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry
Molecular Biology/Genomics [q-bio.GN]
MESH: Mutation
Tumor suppressor gene
[SDV.CAN]Life Sciences [q-bio]/Cancer
[SDV.BC]Life Sciences [q-bio]/Cellular Biology
Biology
[SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics
MESH: Protein-Serine-Threonine Kinases
MESH: Pleural Neoplasms
03 medical and health sciences
[SDV.CAN] Life Sciences [q-bio]/Cancer
MESH: Pyridones
MESH: Cell Proliferation
[SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry
Molecular Biology/Genomics [q-bio.GN]
medicine
MESH: Tumor Suppressor Proteins
Protein kinase B
[SDV.BC] Life Sciences [q-bio]/Cellular Biology
PI3K/AKT/mTOR pathway
MESH: TOR Serine-Threonine Kinases
Hippo signaling pathway
MESH: Humans
MESH: Mesothelioma
Point mutation
MESH: Apoptosis
MESH: Adult
[SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry
Molecular Biology/Molecular biology
MESH: Neoplasm Invasiveness
MESH: Genes
Tumor Suppressor
MESH: Male
MESH: Lung Neoplasms
030104 developmental biology
[SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics
MESH: Pyrimidines
Cancer research
MESH: Female
Zdroj: Clinical Cancer Research
Clinical Cancer Research, 2017, 23 (12), pp.3191-3202. ⟨10.1158/1078-0432.CCR-16-1971⟩
Clinical Cancer Research, American Association for Cancer Research, 2017, 23 (12), pp.3191-3202. ⟨10.1158/1078-0432.CCR-16-1971⟩
ISSN: 1078-0432
1557-3265
DOI: 10.1158/1078-0432.CCR-16-1971⟩
Popis: 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.
Databáze: OpenAIRE
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