Clinicopathological and Genomic Profiles of Atypical Fibroxanthoma and Pleomorphic Dermal Sarcoma Identify Overlapping Signatures with a High Mutational Burden

Abstract

Atypical fibroxanthoma (AFX) and pleomorphic dermal sarcoma (PDS) are rare tumors developing in chronically sun-exposed skin. Clinicopathological features are similar, but they differ in prognosis, while PDS has a more aggressive course with a higher risk for local recurrence and metastases. In current clinical practice, they are diagnosed by exclusion using immunohistochemistry. Thus, stringent diagnostic criteria and correct differentiation are critical in management and treatment for optimal outcomes. This retrospective single-center study collected clinicopathological data and tumor samples of 10 AFX and 18 PDS. Extracted genomic DNA from tumor specimens was analyzed by a next-generation sequencing (NGS) platform (FoundationOne-CDx™). Among 65 identified mutations, TP53 inactivating mutations were observed in all tumor specimens. In both AFX and PDS, the known pathogenic gene alterations in CDKN2A, TERT promoter, and NOTCH1 were frequently present, along with high mutational burden and stable Micro-Satellite Instability status. The mutational profiles differed only in ASXL1, which was only present in AFX. Further differences were identified in likely pathogenic and unknown gene alterations. Similarities in their genomic signatures could help to distinguish them from other malignancies, but they are not distinguishable between each other using the FoundationOne-CDx™ NGS panel. Therefore, histological criteria to determine diagnosis remain valid. For further insight, performing deep tumor profiling may be necessary.

Clear cell variant of atypical fibroxanthoma and pleomorphic dermal sarcoma: Molecular characterization and review of the literature

“…These are thought to be ultraviolet‐induced and are consistent with the variant class (C>T/G>A) most frequently seen in our cases in agreement with tumors arising in chronically sun‐damaged skin. Similar findings have been observed in the majority of AFX and PDS cases subjected to molecular analyses to date 21–25 . Finally, ccPDS and ccAFX also showed no significant MSI, in accordance with a previous report 25 …”

“…However, some differences in genomic alterations were seen between the ccAFX and ccPDS cases. In contrast to the literature, TERT promoter and NOTCH2 mutations, present in the ccAFX but not in the ccPDS case, have previously been shown to occur in the majority of PDS cases 24,25 . In addition, mutations of the APC gene, observed in the ccPDS case only, were reported in 49% of PDS and 42% of AFX cases 25 .…”

“…In contrast to the literature, TERT promoter and NOTCH2 mutations, present in the ccAFX but not in the ccPDS case, have previously been shown to occur in the majority of PDS cases. 24,25 In addition, mutations of the APC gene, observed in the ccPDS case only, were reported in 49% of PDS and 42% of AFX cases. 25 Here, we also identified two variants of unknown significance in the RANBP2 and ZFHX3 genes which were present only in the ccPDS case.…”

“…24,25 In addition, mutations of the APC gene, observed in the ccPDS case only, were reported in 49% of PDS and 42% of AFX cases. 25 Here, we also identified two variants of unknown significance in the RANBP2 and ZFHX3 genes which were present only in the ccPDS case. RANBP2 and ZFHX3 gene alterations have not previously been described in PDS.…”

Glycolysis-Related LINC02432/Hsa-miR-98–5p/HK2 Axis Inhibits Ferroptosis and Predicts Immune Infiltration, Tumor Mutation Burden, and Drug Sensitivity in Pancreatic Adenocarcinoma

“…Recent clinical studies have identified tumor mutation burden (TMB) as an indicator for predicting response to immunotherapy ( Zhang W. et al, 2021 ). High TMB have better response to PD-1/PD-L1 therapy across diverse tumor entities ( Ak et al, 2021 ). Therefore, analyzing the relationship between glycolysis-related ceRNA networks, tumor-infiltrating immunity, TMB and drug sensitivity is critical to explain the potential molecular mechanisms implicated in the development of PAAD, and identify promising biomarkers and novel therapeutic drugs.…”