Molecular Profiling of Thymoma and Thymic Carcinoma: Genetic Differences and Potential Novel Therapeutic Targets

Franz Enkner, Bettina Pichlhöfer, Alexandru Teodor Zaharie, Milica Krunic, Tina Maria Holper, Stefan Janik, Bernhard Moser, Karin Schlangen, Barbara Neudert, Karin Walter, Brigitte Migschitz, Leonhard Müllauer, Franz Enkner, Bettina Pichlhöfer, Alexandru Teodor Zaharie, Milica Krunic, Tina Maria Holper, Stefan Janik, Bernhard Moser, Karin Schlangen, Barbara Neudert, Karin Walter, Brigitte Migschitz, Leonhard Müllauer

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.

Keywords: Immunohistochemistry; Mutation; Thymic carcinoma; Thymoma; miRNA.

Conflict of interest statement

The authors declare that they have no conflict of interest.

Figures

Fig. 1
Fig. 1
Heatmap of all miRNA transcripts differentially expressed in type A thymomas and thymic carcinomas at a false discovery rate p-value 

Fig. 2

Heatmap showing high C19MC miRNA…

Fig. 2

Heatmap showing high C19MC miRNA cluster expression in four of five type A…

Fig. 2
Heatmap showing high C19MC miRNA cluster expression in four of five type A thymomas, but virtually no expression in thymic carcinomas at a false discovery rate p-value 

Fig. 3

Heatmap showing different expression of…

Fig. 3

Heatmap showing different expression of C14MC miRNA cluster members in type A thymomas…

Fig. 3
Heatmap showing different expression of C14MC miRNA cluster members in type A thymomas and thymic carcinomas at a false discovery rate p-value 

Fig. 4

Non-clustered miRNAs with stronger expression…

Fig. 4

Non-clustered miRNAs with stronger expression in thymic carcinomas than in type A thymomas

Fig. 4
Non-clustered miRNAs with stronger expression in thymic carcinomas than in type A thymomas

Fig. 5

Non-clustered miRNAs with lower expression…

Fig. 5

Non-clustered miRNAs with lower expression in thymic carcinomas than in type A thymomas

Fig. 5
Non-clustered miRNAs with lower expression in thymic carcinomas than in type A thymomas

Fig. 6

PDGFRA protein expression in type…

Fig. 6

PDGFRA protein expression in type A and B3 thymomas and thymic carcinomas

Fig. 6
PDGFRA protein expression in type A and B3 thymomas and thymic carcinomas

Fig. 7

PD-L1 protein expression in type…

Fig. 7

PD-L1 protein expression in type A and B3 thymomas and thymic carcinomas

Fig. 7
PD-L1 protein expression in type A and B3 thymomas and thymic carcinomas

Fig. 8

p16 INK4A protein expression in…

Fig. 8

p16 INK4A protein expression in type A and B3 thymomas and thymic carcinomas

Fig. 8
p16INK4A protein expression in type A and B3 thymomas and thymic carcinomas
All figures (8)
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References
    1. Travis WD, Brambilla E, Burke AP, Marx A, Nicholson AG (Eds.) (2015) WHO classification of tumours of the lung, pleura, thymus and heart. IARC Press, Lyon - PubMed
    1. Kelly RJ, Petrini I, Rajan A, Wang Y, Giaccone G. Thymic malignancies: from clinical management to targeted therapies. J Clin Oncol: Off J Am Soc Clin Oncol. 2011;29(36):4820–4827. doi: 10.1200/JCO.2011.36.0487. - DOI - PMC - PubMed
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Fig. 2
Fig. 2
Heatmap showing high C19MC miRNA cluster expression in four of five type A thymomas, but virtually no expression in thymic carcinomas at a false discovery rate p-value 

Fig. 3

Heatmap showing different expression of…

Fig. 3

Heatmap showing different expression of C14MC miRNA cluster members in type A thymomas…

Fig. 3
Heatmap showing different expression of C14MC miRNA cluster members in type A thymomas and thymic carcinomas at a false discovery rate p-value 

Fig. 4

Non-clustered miRNAs with stronger expression…

Fig. 4

Non-clustered miRNAs with stronger expression in thymic carcinomas than in type A thymomas

Fig. 4
Non-clustered miRNAs with stronger expression in thymic carcinomas than in type A thymomas

Fig. 5

Non-clustered miRNAs with lower expression…

Fig. 5

Non-clustered miRNAs with lower expression in thymic carcinomas than in type A thymomas

Fig. 5
Non-clustered miRNAs with lower expression in thymic carcinomas than in type A thymomas

Fig. 6

PDGFRA protein expression in type…

Fig. 6

PDGFRA protein expression in type A and B3 thymomas and thymic carcinomas

Fig. 6
PDGFRA protein expression in type A and B3 thymomas and thymic carcinomas

Fig. 7

PD-L1 protein expression in type…

Fig. 7

PD-L1 protein expression in type A and B3 thymomas and thymic carcinomas

Fig. 7
PD-L1 protein expression in type A and B3 thymomas and thymic carcinomas

Fig. 8

p16 INK4A protein expression in…

Fig. 8

p16 INK4A protein expression in type A and B3 thymomas and thymic carcinomas

Fig. 8
p16INK4A protein expression in type A and B3 thymomas and thymic carcinomas
All figures (8)
Similar articles
Cited by
References
    1. Travis WD, Brambilla E, Burke AP, Marx A, Nicholson AG (Eds.) (2015) WHO classification of tumours of the lung, pleura, thymus and heart. IARC Press, Lyon - PubMed
    1. Kelly RJ, Petrini I, Rajan A, Wang Y, Giaccone G. Thymic malignancies: from clinical management to targeted therapies. J Clin Oncol: Off J Am Soc Clin Oncol. 2011;29(36):4820–4827. doi: 10.1200/JCO.2011.36.0487. - DOI - PMC - PubMed
    1. Schirosi L, Nannini N, Nicoli D, Cavazza A, Valli R, Buti S, Garagnani L, Sartori G, Calabrese F, Marchetti A, Buttitta F, Felicioni L, Migaldi M, Rea F, Di Chiara F, Mengoli M, Rossi G. Activating c-KIT mutations in a subset of thymic carcinoma and response to different c-KIT inhibitors. Ann Oncol: Off J Eur Soc Med Oncol / ESMO. 2012;23(9):2409–2414. doi: 10.1093/annonc/mdr626. - DOI - PubMed
    1. Yoh K, Nishiwaki Y, Ishii G, Goto K, Kubota K, Ohmatsu H, Niho S, Nagai K, Saijo N. Mutational status of EGFR and KIT in thymoma and thymic carcinoma. Lung Cancer. 2008;62(3):316–320. doi: 10.1016/j.lungcan.2008.03.013. - DOI - PubMed
    1. Petrini I, Meltzer PS, Kim IK, Lucchi M, Park KS, Fontanini G, Gao J, Zucali PA, Calabrese F, Favaretto A, Rea F, Rodriguez-Canales J, Walker Rl, Pineda M, Zhu YJ, Lau C, Killian KJ, Bilke S, Voeller D, Dakshanamurthy S, Wang Y, Giaccone G (2014) A specific missense mutation in GTF2I occurs at high frequency in thymic epithelial tumors. Nat Genet 46 (8):844–849. doi:10.1038/Ng.3016. http://Www.Nature.Com/Ng/Journal/V46/N8/Abs/Ng.3016.Html-Supplementary-I... - PMC - PubMed
Show all 67 references
MeSH terms
Supplementary concepts
Related information
Full text links [x]
[x]
Cite
Copy Download .nbib
Format: AMA APA MLA NLM
Fig. 3
Fig. 3
Heatmap showing different expression of C14MC miRNA cluster members in type A thymomas and thymic carcinomas at a false discovery rate p-value 

Fig. 4

Non-clustered miRNAs with stronger expression…

Fig. 4

Non-clustered miRNAs with stronger expression in thymic carcinomas than in type A thymomas

Fig. 4
Non-clustered miRNAs with stronger expression in thymic carcinomas than in type A thymomas

Fig. 5

Non-clustered miRNAs with lower expression…

Fig. 5

Non-clustered miRNAs with lower expression in thymic carcinomas than in type A thymomas

Fig. 5
Non-clustered miRNAs with lower expression in thymic carcinomas than in type A thymomas

Fig. 6

PDGFRA protein expression in type…

Fig. 6

PDGFRA protein expression in type A and B3 thymomas and thymic carcinomas

Fig. 6
PDGFRA protein expression in type A and B3 thymomas and thymic carcinomas

Fig. 7

PD-L1 protein expression in type…

Fig. 7

PD-L1 protein expression in type A and B3 thymomas and thymic carcinomas

Fig. 7
PD-L1 protein expression in type A and B3 thymomas and thymic carcinomas

Fig. 8

p16 INK4A protein expression in…

Fig. 8

p16 INK4A protein expression in type A and B3 thymomas and thymic carcinomas

Fig. 8
p16INK4A protein expression in type A and B3 thymomas and thymic carcinomas
All figures (8)
Fig. 4
Fig. 4
Non-clustered miRNAs with stronger expression in thymic carcinomas than in type A thymomas
Fig. 5
Fig. 5
Non-clustered miRNAs with lower expression in thymic carcinomas than in type A thymomas
Fig. 6
Fig. 6
PDGFRA protein expression in type A and B3 thymomas and thymic carcinomas
Fig. 7
Fig. 7
PD-L1 protein expression in type A and B3 thymomas and thymic carcinomas
Fig. 8
Fig. 8
p16INK4A protein expression in type A and B3 thymomas and thymic carcinomas

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