Journal ArticleDOI
Comprehensive genomic analysis of malignant pleural mesothelioma identifies recurrent mutations, gene fusions and splicing alterations
Raphael Bueno,Eric Stawiski,Leonard D. Goldstein,Steffen Durinck,Assunta De Rienzo,Zora Modrusan,Florian Gnad,Thong T. Nguyen,Bijay S. Jaiswal,Lucian R. Chirieac,Daniele Sciaranghella,Nhien Dao,Corinne E. Gustafson,Kiara J. Munir,Jason A. Hackney,Amitabha Chaudhuri,Ravi Gupta,Joseph Guillory,Karen Toy,Connie Ha,Ying-Jiun Chen,Jeremy Stinson,Subhra Chaudhuri,Na Zhang,Thomas D. Wu,David J. Sugarbaker,Frederic J. de Sauvage,William G. Richards,Somasekar Seshagiri +28 more
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TLDR
Recurrent gene fusions and splice alterations to be frequent mechanisms for inactivation of NF2, BAP1 and SETD2 are found and alterations in Hippo, mTOR, histone methylation, RNA helicase and p53 signaling pathways in MPMs are identified.Abstract:
We analyzed transcriptomes (n = 211), whole exomes (n = 99) and targeted exomes (n = 103) from 216 malignant pleural mesothelioma (MPM) tumors. Using RNA-seq data, we identified four distinct molecular subtypes: sarcomatoid, epithelioid, biphasic-epithelioid (biphasic-E) and biphasic-sarcomatoid (biphasic-S). Through exome analysis, we found BAP1, NF2, TP53, SETD2, DDX3X, ULK2, RYR2, CFAP45, SETDB1 and DDX51 to be significantly mutated (q-score ≥ 0.8) in MPMs. We identified recurrent mutations in several genes, including SF3B1 (∼2%; 4/216) and TRAF7 (∼2%; 5/216). SF3B1-mutant samples showed a splicing profile distinct from that of wild-type tumors. TRAF7 alterations occurred primarily in the WD40 domain and were, except in one case, mutually exclusive with NF2 alterations. We found recurrent gene fusions and splice alterations to be frequent mechanisms for inactivation of NF2, BAP1 and SETD2. Through integrated analyses, we identified alterations in Hippo, mTOR, histone methylation, RNA helicase and p53 signaling pathways in MPMs.read more
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YAP/TAZ at the Roots of Cancer
TL;DR: In this paper, a number of cancer-associated extrinsic and intrinsic cues conspire to overrule the YAP-inhibiting microenvironment of normal tissues, including changes in mechanotransduction, inflammation, oncogenic signaling, and regulation of the Hippo pathway.
Journal ArticleDOI
Ferroptosis: mechanisms, biology and role in disease.
TL;DR: In this paper, the authors provide a critical analysis of the current molecular mechanisms and regulatory networks of ferroptosis, the potential physiological functions of the potential therapeutic roles, and its pathological roles, together with a potential for therapeutic targeting.
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Intercellular interaction dictates cancer cell ferroptosis via NF2–YAP signalling
Jiao Wu,Jiao Wu,Alexander M. Minikes,Alexander M. Minikes,Minghui Gao,Minghui Gao,Huijie Bian,Yong Li,Brent R. Stockwell,Zhi-Nan Chen,Xuejun Jiang +10 more
TL;DR: Ferroptosis in cancer cells can be regulated by cadherin-mediated intercellular contacts, NF2–Hippo signalling, and activity of the YAP transcription co-activator, and this finding provides mechanistic insights into the observations that cancer cells with mesenchymal or metastatic property are highly sensitive to ferroPTosis.
Journal ArticleDOI
Integrative Molecular Characterization of Malignant Pleural Mesothelioma
Julija Hmeljak,Francisco Sanchez-Vega,Katherine A. Hoadley,Juliann Shih,Chip Stewart,David I. Heiman,Patrick S. Tarpey,Ludmila Danilova,Esther Drill,Ewan A. Gibb,Reanne Bowlby,Rupa S. Kanchi,Hatice U. Osmanbeyoglu,Yoshitaka Sekido,Jumpei Takeshita,Yulia Newton,Kiley Graim,Manaswi Gupta,Lixia Diao,David L Gibbs,Vesteinn Thorsson,Lisa Iype,Havish S. Kantheti,David T. Severson,Gloria Ravegnini,Patrice Desmeules,Achim A. Jungbluth,William D. Travis,Sanja Dacic,Lucian R. Chirieac,Françoise Galateau-Sallé,Junya Fujimoto,Aliya N. Husain,Henrique César Santejo Silveira,Valerie W. Rusch,Robert C. Rintoul,Harvey I. Pass,Hedy L. Kindler,Marjorie G. Zauderer,David J. Kwiatkowski,Raphael Bueno,Anne S. Tsao,Jenette Creaney,Tara M. Lichtenberg,Kristen M. Leraas,Jay Bowen,Ina Felau,Jean C. Zenklusen,Rehan Akbani,Andrew D. Cherniack,Lauren Averett Byers,Michael S. Noble,Jonathan A. Fletcher,Gordon Robertson,Ronglai Shen,Hiroyuki Aburatani,Bruce W. S. Robinson,Peter J. Campbell,Marc Ladanyi +58 more
TL;DR: A comprehensive integrated genomic study of 74 MPMs provided a deeper understanding of histology-independent determinants of aggressive behavior, defined a novel genomic subtype with TP53 and SETDB1 mutations and extensive loss of heterozygosity, and discovered strong expression of the immune-checkpoint gene VISTA in epithelioid MPM.
Journal ArticleDOI
Tremelimumab as second-line or third-line treatment in relapsed malignant mesothelioma (DETERMINE): a multicentre, international, randomised, double-blind, placebo-controlled phase 2b trial.
Michele Maio,Arnaud Scherpereel,Luana Calabrò,Joachim G.J.V. Aerts,Susana Cedres Perez,Alessandra Bearz,Kristiaan Nackaerts,Dean A. Fennell,Dariusz M. Kowalski,Anne S. Tsao,Paul D. Taylor,Federica Grosso,Scott J. Antonia,Anna K. Nowak,Anna K. Nowak,Maria Taboada,Martina Puglisi,Paul K. Stockman,Hedy L. Kindler +18 more
TL;DR: The DETERMINE study investigated the effects of the cytotoxic-T-lymphocyte-associated antigen 4 (CTLA-4) monoclonal antibody tremelimumab in patients with previously treated advanced malignant mesothelioma and overall survival was overall survival in the intention-to-treat population.
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