title: Overexpression and promoter mutation of the TERT gene in malignant pleural mesothelioma.
abstract: Malignant pleural mesothelioma (MPM) is a very aggressive tumor with no known curative treatment. Better knowledge of the molecular mechanisms of mesothelial carcinogenesis is required to develop new therapeutic strategies. MPM, like all cancer cells, needs to maintain telomere length to prevent senescence. Previous studies suggested that the telomere lengthening mechanism in MPM is based mainly on telomerase activity. For this reason, we focused on the key catalytic enzyme, TERT (telomerase reverse transcriptase), by analyzing its gene expression in MPM and by studying the mechanism underlying its upregulation. We used our large collection of MPM composed of 61 MPM in culture and 71 frozen MPM tumor samples. Evaluation of TERT mRNA expression by quantitative RT-PCR showed overexpression in MPM in culture compared with normal mesothelial cells, and in MPM tumor samples compared with normal pleura. We identified a 'hot spot' of mutations in the TERT gene core promoter in both MPM in culture and in MPM tumor samples with an overall frequency of 15%. Furthermore, data clearly identified mutation in the TERT promoter as a mechanism of TERT mRNA upregulation in MPM. In contrast, gene copy number amplification was not associated with TERT overexpression. Then, we analyzed the clinicopathological, etiological and genetic characteristics of MPM with mutations in the TERT promoter. TERT promoter mutations were more frequent in MPM with sarcomatoid histologic subtype (P<0.01), and they were frequently associated with CDKN2A gene inactivation (P=0.03). In conclusion, a subgroup of MPM presents TERT promoter mutations, which lead to TERT mRNA upregulation. This is the first recurrent gain-of-function oncogenic mutations identified in MPM.
authors: 1] INSERM, UMR-674, IUH, Paris, France [2] Université Paris Descartes, Labex Immuno-oncology, Sorbonne Paris Cité, Faculté de Médecine, Paris, France.
authors: A
authors: A
authors: Tallet
authors: 1] INSERM, UMR-674, IUH, Paris, France [2] Université Paris Descartes, Labex Immuno-oncology, Sorbonne Paris Cité, Faculté de Médecine, Paris, France.
authors: J-C
authors: JC
authors: Nault
authors: 1] INSERM, UMR-674, IUH, Paris, France [2] Université Paris Descartes, Labex Immuno-oncology, Sorbonne Paris Cité, Faculté de Médecine, Paris, France.
authors: A
authors: A
authors: Renier
authors: CHRU Lille, Service de Chirurgie Cardiaque, Lille, France.
authors: I
authors: I
authors: Hysi
authors: 1] CHU Caen, Service d'Anatomo-Pathologie, Caen, France [2] INSERM, U1086, Caen, France.
authors: F
authors: F
authors: Galateau-Sallé
authors: AP-HP, GHU Ouest, Hôpital Européen Georges Pompidou, Laboratoire d'Anatomie Pathologique, Paris, France.
authors: A
authors: A
authors: Cazes
authors: CHRU Lille, Université de Lille II, Institut Pathologie, Centre de Biologie-Pathologie, Lille, France.
authors: M-C
authors: MC
authors: Copin
authors: CHU Nice, Laboratoire de Pathologie Clinique et Expérimentale (LPCE) et Biobanque Humaine, Hôpital Pasteur, Nice, France.
authors: P
authors: P
authors: Hofman
authors: 1] Centre Hospitalier Intercommunal de Créteil, Service de Pneumologie et de Pathologie Professionnelle, Créteil, France [2] INSERM, U955, Equipe 4, Créteil, France.
authors: P
authors: P
authors: Andujar
authors: 1] INSERM, UMR-674, IUH, Paris, France [2] Université Paris Descartes, Labex Immuno-oncology, Sorbonne Paris Cité, Faculté de Médecine, Paris, France [3] AP-HP, GHU Ouest, Hôpital Européen Georges Pompidou, Service de Chirurgie Thoracique, Paris, France.
authors: F
authors: F
authors: Le Pimpec-Barthes
authors: 1] INSERM, UMR-674, IUH, Paris, France [2] Université Paris Descartes, Labex Immuno-oncology, Sorbonne Paris Cité, Faculté de Médecine, Paris, France.
authors: J
authors: J
authors: Zucman-Rossi
authors: 1] INSERM, UMR-674, IUH, Paris, France [2] Université Paris Descartes, Labex Immuno-oncology, Sorbonne Paris Cité, Faculté de Médecine, Paris, France.
authors: M-C
authors: MC
authors: Jaurand
authors: 1] INSERM, UMR-674, IUH, Paris, France [2] Université Paris Descartes, Labex Immuno-oncology, Sorbonne Paris Cité, Faculté de Médecine, Paris, France.
authors: D
authors: D
authors: Jean
mesh_terms: D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008175:Lung Neoplasms / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D008654:Mesothelioma / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D000086002:Mesothelioma, Malignant; D009154:Mutation; D010997:Pleural Neoplasms / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D011401:Promoter Regions, Genetic / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D019098:Telomerase / Q000235:genetics*
chemical_list: D012333:RNA, Messenger; D019098:Telomerase