title: Molecular Profiling of Thymoma and Thymic Carcinoma: Genetic Differences and Potential Novel Therapeutic Targets.
abstract: Thymoma and thymic carcinoma are thymic epithelial tumors (TETs). We performed a molecular profiling to investigate the pathogenesis of TETs and identify novel targets for therapy. We analyzed 37 thymomas (18 type A, 19 type B3) and 35 thymic carcinomas. The sequencing of 50 genes detected nonsynonymous mutations in 16 carcinomas affecting ALK, ATM, CDKN2A, ERBB4, FGFR3, KIT, NRAS and TP53. Only two B3 thymomas had a mutation in noncoding regions of the SMARCB1 and STK11 gene respectively. Three type A thymomas harbored a nonsynonymous HRAS mutation. Fluorescence in situ hybridization detected in 38 % of carcinomas a CDKN2A, in 32 % a TP53 and in 8 % an ATM gene deletion, whereas only one B3 thymoma exhibited a CDKNA deletion, and none of the type A thymomas showed a gene loss. Sequencing of the total miRNA pool of 5 type A thymomas and 5 thymic carcinomas identified the C19MC miRNA cluster as highly expressed in type A thymomas, but completely silenced in thymic carcinomas. Furthermore, the miRNA cluster C14MC was downregulated in thymic carcinomas. Among non-clustered miRNAs, the upregulation of miR-21, miR-9-3 and miR-375 and the downregulation of miR-34b, miR-34c, miR-130a and miR-195 in thymic carcinomas were most significant. The expression of ALK, HER2, HER3, MET, phospho-mTOR, p16INK4A, PDGFRA, PDGFRB, PD-L1, PTEN and ROS1 was investigated by immunohistochemistry. PDGFRA was increased in thymic carcinomas and PD-L1 in B3 thymomas and thymic carcinomas. In summary, our results reveal genetic differences between thymomas and thymic carcinomas and suggest potential novel targets for therapy.
authors.affiliation: Department of Pathology, Medical University Vienna, Währinger Gürtel 18-20, 1090, Vienna, Austria.
authors.forename: Franz
authors.initials: F
authors.lastname: Enkner
authors.affiliation: Department of Pathology, Medical University Vienna, Währinger Gürtel 18-20, 1090, Vienna, Austria.
authors.forename: Bettina
authors.initials: B
authors.lastname: Pichlhöfer
authors.affiliation: Department of Pathology, Medical University Vienna, Währinger Gürtel 18-20, 1090, Vienna, Austria.
authors.forename: Alexandru Teodor
authors.initials: AT
authors.lastname: Zaharie
authors.affiliation: Center for Integrative Bioinformatics Vienna, Max F. Perutz Laboratories, University of Vienna and Medical University Vienna, Vienna, Austria.
authors.forename: Milica
authors.initials: M
authors.lastname: Krunic
authors.affiliation: Department of Pathology, Medical University Vienna, Währinger Gürtel 18-20, 1090, Vienna, Austria.
authors.forename: Tina Maria
authors.initials: TM
authors.lastname: Holper
authors.affiliation: Department of Thoracic Surgery, Medical University Vienna, Währinger Gürtel 18-20, 1090, Vienna, Austria.
authors.forename: Stefan
authors.initials: S
authors.lastname: Janik
authors.affiliation: Department of Thoracic Surgery, Medical University Vienna, Währinger Gürtel 18-20, 1090, Vienna, Austria.
authors.forename: Bernhard
authors.initials: B
authors.lastname: Moser
authors.affiliation: Center for Medical Statistics, Informatics, and Intelligent Systems, Section for Biosimulation and Bioinformatic, Medical University Vienna, Währinger Gürtel 18-20, 1090, Vienna, Austria.
authors.forename: Karin
authors.initials: K
authors.lastname: Schlangen
authors.affiliation: Department of Pathology, Medical University Vienna, Währinger Gürtel 18-20, 1090, Vienna, Austria.
authors.forename: Barbara
authors.initials: B
authors.lastname: Neudert
authors.affiliation: Department of Pathology, Medical University Vienna, Währinger Gürtel 18-20, 1090, Vienna, Austria.
authors.forename: Karin
authors.initials: K
authors.lastname: Walter
authors.affiliation: Department of Pathology, Medical University Vienna, Währinger Gürtel 18-20, 1090, Vienna, Austria.
authors.forename: Brigitte
authors.initials: B
authors.lastname: Migschitz
authors.affiliation: Department of Pathology, Medical University Vienna, Währinger Gürtel 18-20, 1090, Vienna, Austria. leonhard.muellauer@meduniwien.ac.at.
authors.forename: Leonhard
authors.initials: L
authors.lastname: Müllauer
mesh_terms: D014408:Biomarkers, Tumor / Q000235:genetics; D006801:Humans; D007150:Immunohistochemistry / Q000379:methods; D017404:In Situ Hybridization, Fluorescence / Q000379:methods; D035683:MicroRNAs / Q000235:genetics; D009154:Mutation / Q000235:genetics*; D009375:Neoplasms, Glandular and Epithelial / Q000235:genetics; D013945:Thymoma / Q000235:genetics*; D013953:Thymus Neoplasms / Q000235:genetics
chemical_list: D014408:Biomarkers, Tumor; D035683:MicroRNAs
keywords: Immunohistochemistry; Mutation; Thymic carcinoma; Thymoma; miRNA