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. 2016 Apr 19;7(16):21763-74.
doi: 10.18632/oncotarget.7845.

Oncogene and therapeutic target analyses in atypical fibroxanthomas and pleomorphic dermal sarcomas

Doris Helbig  1 , Michaela Angelika Ihle  2 , Katharina Pütz  2 , Iliana Tantcheva-Poor  1 , Cornelia Mauch  1 , Reinhard Büttner  2 , Alexander Quaas  2
Affiliations

Oncogene and therapeutic target analyses in atypical fibroxanthomas and pleomorphic dermal sarcomas

Doris Helbig et al. Oncotarget. .

Abstract

Background: Until now, almost nothing is known about the tumorigenesis of atypical fibroxanthoma (AFX) and pleomorphic dermal sarcoma (PDS). Our hypothesis is that AFX is the non-infiltrating precursor lesion of PDS.

Materials and methods: We performed the world-wide most comprehensive immunohistochemical and mutational analysis in well-defined AFX (n=5) and PDS (n=5).

Results: In NGS-based mutation analyses of selected regions by a 17 hotspot gene panel of 102 amplicons we could detect TP53 mutations in all PDS as well as in the only analyzed AFX and PDS of the same patient. Besides, we detected mutations in the CDKN2A, HRAS, KNSTRN and PIK3CA genes.Performing immunohistochemistry for CTNNB1, KIT, CDK4, c-MYC, CTLA-4, CCND1, EGFR, EPCAM, ERBB2, IMP3, INI-1, MKI67, MDM2, MET, p40, TP53, PD-L1 and SOX2 overexpression of TP53, CCND1 and CDK4 was seen in AFX as well as in PDS. IMP3 was upregulated in 2 AFX (weak staining) and 4 PDS (strong staining).FISH analyses for the genes FGFR1, FGFR2 and FGFR3 revealed negative results in all tumors.

Conclusions: UV-induced TP53 mutations as well as CCND1/CDK4 changes seem to play essential roles in tumorigenesis of PDS. Furthermore, we found some more interesting mutated genes in other oncogene pathways (activating mutations of HRAS and PIK3CA). All AFX and PDS investigated immunohistochemically presented with similar oncogene expression profiles (TP53, CCND1, CDK4 overexpression) and the single case with an AFX and PDS showed complete identical TP53 and PIK3CA mutation profiles in both tumors. This reinforces our hypothesis that AFX is the non-infiltrating precursor lesion of PDS.

Keywords: CCND1; CDK4; TP53; atypical fibroxanthoma; pleomorphic dermal sarcoma.

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Conflict of interest statement

Conflicts of Interest and Source of Funding: There is no conflicts of interest. The study protocol conformed to the ethical guidelines of the 1975 Declaration of Helsinki as reflected by the approval of the institution's human research review committee (Registration No. 15-307). All subjects gave consent prior to participation in this study.

Figures

Figure 1
Figure 1. Representative AFX (case 4): a. 40xHE; b. 40xp53; c. 40xCyclin D1; d. 40xCDK4; e. 40xIMP3
Figure 2
Figure 2. Representative PDS (case 8): a. 40xHE; b. 40xp53; c. 40xCyclin D1; d. 40xCDK4; e. 40xIMP3
Figure 3
Figure 3. TP53 mutational analyses
TP53 exons 5-8 were analyzed by Next Generation Sequencing. Integrative genomic viewer visualization of all detected TP53 mutations in AFX and PDS. In case 8, the tumor content was too low for mutation analyses (<10%).
See this image and copyright information in PMC

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