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.
Highlights
IntroductionThymic epithelial tumors (TETs) are rare mediastinal tumors
Electronic supplementary material The online version of this article contains supplementary material, which is available to authorized users.Thymic epithelial tumors (TETs) are rare mediastinal tumors
We explored the thymomas and thymic carcinomas with a panel of immunohistochemical stains for antigens (ALK, HER2, HER3, MET, phospho-mTOR, p16INK4A, PDGFRA, PDGFRB, PD-L1, PTEN, and ROS1) that might constitute putative targets for therapy and fluorescence in situ hybridization for ALK, ATM, CDKN2A, fibroblast growth factor receptor 3 (FGFR3) and TP53, to detect rearrangements and/or numerical aberrations of these genes
Summary
Thymic epithelial tumors (TETs) are rare mediastinal tumors. The WHO classification distinguishes type A, AB, B1, B2 and B3 thymomas and rare other subtypes from thymic carcinomas [1]. Thymic carcinoma on the contrary is a highly aggressive tumor with frequent lymphatic and hematogenous metastasis. Mutation of the tyrosine kinase KIT was the only known targetable alteration in thymic carcinoma, but it is present in only 6–12 % of cases [3, 4]. Whole exome and targeted gene panel sequencing of TETs identified a specific missense mutation in GTF2I in type A thymomas and common mutations in TP53 and epigenetic regulatory genes in thymic carcinomas [5,6,7,8]
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