title: Comprehensive genomic analysis of malignant pleural mesothelioma identifies recurrent mutations, gene fusions and splicing alterations.
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.
authors.affiliation: Division of Thoracic Surgery, The Lung Center and the International Mesothelioma Program, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Raphael
authors.initials: R
authors.lastname: Bueno
authors.affiliation: Bioinformatics and Computational Biology Department, Genentech, Inc., South San Francisco, California, USA.|Molecular Biology Department, Genentech, Inc., South San Francisco, California, USA.
authors.forename: Eric W
authors.initials: EW
authors.lastname: Stawiski
authors.affiliation: Bioinformatics and Computational Biology Department, Genentech, Inc., South San Francisco, California, USA.|Molecular Biology Department, Genentech, Inc., South San Francisco, California, USA.
authors.forename: Leonard D
authors.initials: LD
authors.lastname: Goldstein
authors.affiliation: Bioinformatics and Computational Biology Department, Genentech, Inc., South San Francisco, California, USA.|Molecular Biology Department, Genentech, Inc., South San Francisco, California, USA.
authors.forename: Steffen
authors.initials: S
authors.lastname: Durinck
authors.affiliation: Division of Thoracic Surgery, The Lung Center and the International Mesothelioma Program, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Assunta
authors.initials: A
authors.lastname: De Rienzo
authors.affiliation: Molecular Biology Department, Genentech, Inc., South San Francisco, California, USA.
authors.forename: Zora
authors.initials: Z
authors.lastname: Modrusan
authors.affiliation: Bioinformatics and Computational Biology Department, Genentech, Inc., South San Francisco, California, USA.
authors.forename: Florian
authors.initials: F
authors.lastname: Gnad
authors.affiliation: Molecular Biology Department, Genentech, Inc., South San Francisco, California, USA.
authors.forename: Thong T
authors.initials: TT
authors.lastname: Nguyen
authors.affiliation: Molecular Biology Department, Genentech, Inc., South San Francisco, California, USA.
authors.forename: Bijay S
authors.initials: BS
authors.lastname: Jaiswal
authors.affiliation: Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Lucian R
authors.initials: LR
authors.lastname: Chirieac
authors.affiliation: Division of Thoracic Surgery, The Lung Center and the International Mesothelioma Program, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Daniele
authors.initials: D
authors.lastname: Sciaranghella
authors.affiliation: Division of Thoracic Surgery, The Lung Center and the International Mesothelioma Program, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Nhien
authors.initials: N
authors.lastname: Dao
authors.affiliation: Division of Thoracic Surgery, The Lung Center and the International Mesothelioma Program, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Corinne E
authors.initials: CE
authors.lastname: Gustafson
authors.affiliation: Division of Thoracic Surgery, The Lung Center and the International Mesothelioma Program, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Kiara J
authors.initials: KJ
authors.lastname: Munir
authors.affiliation: Bioinformatics and Computational Biology Department, Genentech, Inc., South San Francisco, California, USA.
authors.forename: Jason A
authors.initials: JA
authors.lastname: Hackney
authors.affiliation: Bioinformatics Department, MedGenome Labs, Pvt., Ltd., Narayana Health City, Bangalore, India.
authors.forename: Amitabha
authors.initials: A
authors.lastname: Chaudhuri
authors.affiliation: Bioinformatics Department, MedGenome Labs, Pvt., Ltd., Narayana Health City, Bangalore, India.
authors.forename: Ravi
authors.initials: R
authors.lastname: Gupta
authors.affiliation: Molecular Biology Department, Genentech, Inc., South San Francisco, California, USA.
authors.forename: Joseph
authors.initials: J
authors.lastname: Guillory
authors.affiliation: Molecular Biology Department, Genentech, Inc., South San Francisco, California, USA.
authors.forename: Karen
authors.initials: K
authors.lastname: Toy
authors.affiliation: Molecular Biology Department, Genentech, Inc., South San Francisco, California, USA.
authors.forename: Connie
authors.initials: C
authors.lastname: Ha
authors.affiliation: Molecular Biology Department, Genentech, Inc., South San Francisco, California, USA.
authors.forename: Ying-Jiun
authors.initials: YJ
authors.lastname: Chen
authors.affiliation: Molecular Biology Department, Genentech, Inc., South San Francisco, California, USA.
authors.forename: Jeremy
authors.initials: J
authors.lastname: Stinson
authors.affiliation: Molecular Biology Department, Genentech, Inc., South San Francisco, California, USA.
authors.forename: Subhra
authors.initials: S
authors.lastname: Chaudhuri
authors.affiliation: Molecular Biology Department, Genentech, Inc., South San Francisco, California, USA.
authors.forename: Na
authors.initials: N
authors.lastname: Zhang
authors.affiliation: Bioinformatics and Computational Biology Department, Genentech, Inc., South San Francisco, California, USA.
authors.forename: Thomas D
authors.initials: TD
authors.lastname: Wu
authors.affiliation: Division of Thoracic Surgery, Baylor College of Medicine, Houston, Texas, USA.
authors.forename: David J
authors.initials: DJ
authors.lastname: Sugarbaker
authors.affiliation: Molecular Oncology Department, Genentech, Inc., South San Francisco, California, USA.
authors.forename: Frederic J
authors.initials: FJ
authors.lastname: de Sauvage
authors.affiliation: Division of Thoracic Surgery, The Lung Center and the International Mesothelioma Program, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: William G
authors.initials: WG
authors.lastname: Richards
authors.affiliation: Molecular Biology Department, Genentech, Inc., South San Francisco, California, USA.
authors.forename: Somasekar
authors.initials: S
authors.lastname: Seshagiri
mesh_terms: D017398:Alternative Splicing; D045744:Cell Line, Tumor; D004252:DNA Mutational Analysis; D059472:Exome; D006801:Humans; D053208:Kaplan-Meier Estimate; D008175:Lung Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000401:mortality; D008654:Mesothelioma / Q000235:genetics* / Q000378:metabolism / Q000401:mortality; D000086002:Mesothelioma, Malignant; D009154:Mutation; D015514:Oncogene Proteins, Fusion / Q000235:genetics* / Q000378:metabolism; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism; D010997:Pleural Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000401:mortality; D020641:Polymorphism, Single Nucleotide; D016016:Proportional Hazards Models; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D000072260:RNA Splicing Factors; D017413:Ribonucleoprotein, U2 Small Nuclear / Q000235:genetics / Q000378:metabolism
chemical_list: D015514:Oncogene Proteins, Fusion; D010750:Phosphoproteins; D020033:Protein Isoforms; D000072260:RNA Splicing Factors; D017413:Ribonucleoprotein, U2 Small Nuclear; C112491:SF3B1 protein, human