Gene Expression Profile (GEP) Comparison of Atypical Fibroxanthoma (AFX) and Pleomorphic Dermal Sarcoma (PDS)

<b>Background/Objectives</b>: Atypical fibroxanthoma (AFX) and cutaneous undifferentiated pleomorphic sarcoma (cUPS)/pleomorphic dermal sarcoma (PDS) are related dermal neoplasms of uncertain histogenesis that occupy opposite ends of a shared clinical and histopathologic spectrum, with AFX displaying typically low-grade behavior and PDS representing its more aggressive counterpart. The recent literature has confirmed that AFX and PDS also overlap at the molecular and genomic levels; however, little is known about their gene-expression profiles. <b>Methods</b>: We performed gene-expression profiling using RNA sequencing with a Pan-Cancer RNA Panel on a small series of AFX and PDS samples. <b>Results</b>: Unsupervised cluster analysis showed a clear separation between the two groups. We confirmed a TP53 UV-radiation signature in both. However, while AFX and PDS share common DNA mutation profiles in our cohort, RNA sequencing reveals distinct gene-expression signatures that may aid in differentiating these related tumors. In particular, the MAPK pathway, cell adhesion, DNA repair, EMT-like signatures and inflammatory responses play key roles in distinguishing the two groups, at least in our limited cohort, consistent with their differing biological behavior. Differences in the expression of receptor tyrosine kinases were also observed. <b>Conclusions</b>: Gene-expression profiling have the potential to be a valuable tool for distinguishing AFX from PDS, clarifying their positions at opposite ends of a spectrum and providing deeper insight into the biology of these neoplasms.