title: Oncogene and therapeutic target analyses in atypical fibroxanthomas and pleomorphic dermal sarcomas.
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.
  
  
  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.
authors.affiliation: Department of Dermatology, University Hospital Cologne, Cologne, Germany.
authors.forename: Doris
authors.initials: D
authors.lastname: Helbig
authors.affiliation: Institute of Pathology, University Hospital Cologne, Cologne, Germany.
authors.forename: Michaela Angelika
authors.initials: MA
authors.lastname: Ihle
authors.affiliation: Institute of Pathology, University Hospital Cologne, Cologne, Germany.
authors.forename: Katharina
authors.initials: K
authors.lastname: Pütz
authors.affiliation: Department of Dermatology, University Hospital Cologne, Cologne, Germany.
authors.forename: Iliana
authors.initials: I
authors.lastname: Tantcheva-Poor
authors.affiliation: Department of Dermatology, University Hospital Cologne, Cologne, Germany.
authors.forename: Cornelia
authors.initials: C
authors.lastname: Mauch
authors.affiliation: Institute of Pathology, University Hospital Cologne, Cologne, Germany.
authors.forename: Reinhard
authors.initials: R
authors.lastname: Büttner
authors.affiliation: Institute of Pathology, University Hospital Cologne, Cologne, Germany.
authors.forename: Alexander
authors.initials: A
authors.lastname: Quaas
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000235:genetics* / Q000378:metabolism; D004252:DNA Mutational Analysis; D005260:Female; D059014:High-Throughput Nucleotide Sequencing / Q000379:methods; D006801:Humans; D007150:Immunohistochemistry; D017404:In Situ Hybridization, Fluorescence; D008297:Male; D009154:Mutation; D009857:Oncogenes / Q000235:genetics*; D012509:Sarcoma / Q000235:genetics* / Q000378:metabolism; D012878:Skin Neoplasms / Q000235:genetics* / Q000378:metabolism; D014973:Xanthomatosis / Q000235:genetics* / Q000378:metabolism
chemical_list: D014408:Biomarkers, Tumor
keywords: CCND1; CDK4; TP53; atypical fibroxanthoma; pleomorphic dermal sarcoma