Genomic analysis of atypical fibroxanthoma

Abstract

Atypical fibroxanthoma (AFX), is a rare type of skin cancer affecting older individuals with sun damaged skin. Since there is limited genomic information about AFX, our study seeks to improve the understanding of AFX through whole-exome and RNA sequencing of 8 matched tumor-normal samples. AFX is a highly mutated malignancy with recurrent mutations in a number of genes, including COL11A1, ERBB4, CSMD3, and FAT1. The majority of mutations identified were UV signature (C>T in dipyrimidines). We observed deletion of chromosomal segments on chr9p and chr13q, including tumor suppressor genes such as KANK1 and CDKN2A, but no gene fusions were found. Gene expression profiling revealed several biological pathways that are upregulated in AFX, including tumor associated macrophage response, GPCR signaling, and epithelial to mesenchymal transition (EMT). To further investigate the presence of EMT in AFX, we conducted a gene expression meta-analysis that incorporated RNA-seq data from dermal fibroblasts and keratinocytes. Ours is the first study to employ high throughput sequencing for molecular profiling of AFX. These data provide valuable insights to inform models of carcinogenesis and additional research towards tumor-directed therapy.

Genome-wide methylation profiling and copy number analysis in atypical fibroxanthomas and pleomorphic dermal sarcomas indicate a similar molecular phenotype

“…Recently, a next-generation sequencing based study on a considerable number of AFX and PDS expanded the overlapping mutational pattern to NOTCH1 / 2 and FAT1 [27]. However, only a single whole-exome study of AFX has been presented so far [30]. Thus, further whole-exome/genome studies with larger sample numbers of both AFX and PDS will be required to fully understand the genetic underpinnings of these tumors.…”

“…Our study does not provide a final decision on the ongoing debate regarding the histogenesis of AFX and PDS. Many experts assume that AFX and PDS derive from a mesenchymal origin [1, 4], whereas others suggest that AFX may derive from an epithelial origin [30, 35]. This theory was initially introduced by older studies describing clinicopathological similarities between AFX and cSCC with a sarcomatoid dedifferentiation [36, 37].…”

Atypical fibroxanthoma and pleomorphic dermal sarcoma: A reappraisal

“…On the contrary, a more recent study found that EMT is upregulated in AFX. Since EMT is associated with progression and metastasis, the authors suggest that this could explain the recurrences or, more rarely, metastases observed in AFX and PDS 19 . Unfortunately, this study investigated a low number of cases, without indication of their follow-up.…”

CD10 and p63 expression in a sarcomatoid undifferentiated melanoma: A cautionary (and molecularly annotated) tale

“…They also show a wide range of DNA copy number alterations, with greater copy number variations in PDS than in AFX, which has fostered discussion as to whether PDS represents progression of AFX and not a distinct neoplasm . Furthermore, these entities show occasional chromosome 9p deletions and rarer MYC amplifications that are seen in cutaneous melanomas . To the best of our knowledge, however, HRAS and KRAS oncogenic mutations have been discovered in only a small number of PDS and not in AFX .…”

“…Some melanoma variants are strongly associated with additional mutations, including KIT mutations present in mucosal and acral lentiginous melanomas, and NF1 mutations which have been associated with a subset of desmoplastic melanomas . In contrast, AFX has a higher frequency of mutations involving NOTCH1/2, FAT1, COL11A1, CSMD3 , and ERBB4 …”