Copy number variations in atypical fibroxanthomas and pleomorphic dermal sarcomas

Abstract

Atypical fibroxanthomas (AFX) and pleomorphic dermal sarcomas (PDS) are frequent cutaneous sarcomas typically arising on sun-exposed skin in elderly patients. In contrast to AFX, which generally do not recur after complete excision, PDS locally recur in up to 50% and metastasize in up to 20%.We recently detected characteristic UV-induced TP53 mutations as potential driver mutation in almost all PDS investigated as well as activating PIK3CA and RAS gene mutations in around one third of our tumors representing targets for personalized treatments in patients with unresectable or metastasized PDS.In the present study, we identified amplifications and deletions in a small part of the PDS (6 of 27 cases) but not in AFX suggesting that copy number variations (CNV) might not be an initial event in tumor development but rather important during tumor progression. In addition to BRAF, KNSTRN, IDH1 and PDGFRA amplification, CNV analyses revealed deletions in the CDKN2A, KIT and PDGFRA genes. In cases where an appropriate FISH assay was established, the CNV results could be verified by FISH analysis.Amplification of BRAF, KIT or PDGFRA and/or losses of CDKN2A might represent bad prognostic markers, although larger studies are needed to clarify their association with prognosis or progression in PDS.

Immunohistochemical expression of melanocytic and myofibroblastic markers and their molecular correlation in atypical fibroxanthomas and pleomorphic dermal sarcomas

“…Performing NGS with a coverage of >2000 and a tumor fraction of almost always >80%, these mutations are reliably detected. The TP53 mutation detected in the PDS is concordant with our recent investigations in PDS showing characteristic UV‐dependent TP53 mutations in almost all PDS leading to a non‐functional TP53 protein …”

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

“…As in melanoma, AFX, and PDS show a high ultraviolet mutational burden, sometimes involving the TERT promoter and TP53 coding regions . 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 .…”

“…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 .…”

Extended surgical safety margins and ulceration are associated with an improved prognosis in pleomorphic dermal sarcomas

“…On a molecular level, PDS harbour a high mutational burden exhibiting frequent mutations with UV signature in the TP53, TERT, FAT1, HRAS, PIK3CA, KNSTRN, CDKN2A, as well as NOTCH1 and 2 gene, thereby highlighting the role of UV exposure in its etiopathogenesis . Copy number variations (CNV) have been detected in a small part of PDS suggesting that they might not be an initial event in tumour development but gain importance during tumour progression …”

“…4,5 Copy number variations (CNV) have been detected in a small part of PDS suggesting that they might not be an initial event in tumour development but gain importance during tumour progression. 5,6 Despite the fact that PDS have a noteworthy potential to recur as well as to metastasize, there are no clinical guidelines for the follow-up of these patients. There are only a few small descriptive case series, which reported associations between incomplete excision, necrosis, lymphovascular as well as perineural invasion of the PDS and its propensity to metastasis.…”