Alternative PDGFD rearrangements in dermatofibrosarcomas protuberans without PDGFB fusions

Abstract

Dermatofibrosarcoma protuberans is underlined by recurrent collagen type I alpha 1 chain-platelet-derived growth factor B chain (COL1A1-PDGFB) fusions but ~ 4% of typical dermatofibrosarcoma protuberans remain negative for this translocation in routine molecular screening. We investigated a series of 21 cases not associated with the pathognomonic COL1A1-PDGFB fusion on routine fluorescence in situ hybridization (FISH) testing. All cases displayed morphological and clinical features consistent with the diagnosis of dermatofibrosarcoma protuberans. RNA-sequencing analysis was successful in 20 cases. The classical COL1A1-PDGFB fusion was present in 40% of cases (n = 8/20), and subsequently confirmed with a COL1A1 break-apart FISH probe in all but one case (n = 7/8). 55% of cases (n = 11/20) displayed novel PDGFD rearrangements; PDGFD being fused either to the 5' part of COL6A3 (2q37.3) (n = 9/11) or EMILIN2 (18p11) (n = 2/11). All rearrangements led to in-frame fusion transcripts and were confirmed at genomic level by FISH and/or array-comparative genomic hybridization. PDGFD-rearranged dermatofibrosarcoma protuberans presented clinical outcomes similar to typical dermatofibrosarcoma protuberans. Notably, the two EMILIN2-PDGFD cases displayed fibrosarcomatous transformation and homozygous deletions of CDKN2A at genomic level. We report the first recurrent molecular variant of dermatofibrosarcoma protuberans involving PDGFD, which functionally mimic bona fide COL1A1-PDGFB fusions, leading presumably to a similar autocrine loop-stimulating PDGFRB. This study also emphasizes that COL1A1-PDGFB fusions can be cytogenetically cryptic on FISH testing in a subset of cases, thereby representing a diagnostic pitfall that pathologists should be aware of.

A novel case of an aggressive superficial spindle cell sarcoma in an adult resembling fibrosarcomatous dermatofibrosarcoma protuberans and harboring an EML4‐NTRK3 fusion

“…Also, it should be noted that a very small percentage of DFSPs do not appear to exhibit the classic COL1A1‐PDGFB fusion. Recently, it has been discovered that over half of these DFSPs instead harbor rearrangements of PDGFD , and another 40% have cryptogenic COL1A1‐PDGFB fusions . While it is possible that our case represents a DFSP with a novel translocation, the increasing evidence is that this is not the case.…”

S1 guidelines for dermatofibrosarcoma protuberans (DFSP) – update 2018

“…A special DFSP variant is associated with a COL6A3‐PDGFD fusion gene and typically occurs on the breast of females . There have also been some reports of DFSP patients with an EMILIN2‐PDGFD fusion gene . Knowledge about these molecular changes allows for targeted therapy of DFSP.…”

“…The first agent to be approved for systemic treatment of DFSP is the multikinase inhibitor imatinib, showing objective response rates of about 50 % in clinical trials. mit einer EMILIN2-PDGFD-Genfusion beschrieben [8]…”

A novel MAP3K7CL‐ERG fusion in a molecularly confirmed case of dermatofibrosarcoma protuberans with fibrosarcomatous transformation

“…The in‐frame fusion of the 5′ end of COL1A1 to the 3′ end of PDGFB is present in greater than 90% of DFSPs when a combination of FISH and reverse transcription polymerase chain reaction (RT‐PCR) techniques are employed . Two recent studies showed that in the approximately 4% of cases that are negative for this fusion in initial routine testing, RNA sequencing analysis has shown that 40% of cases do indeed have the classical COL1A1 ‐ PDGFB fusion, but another 55% of cases show a fusion between PDGFD and either COL6A3 or EMILIN2 . Cytogenetically, the COL1A1 ‐ PDGFB fusion is frequently in the form of a supernumerary ring chromosome; less often it is found as a linear translocation derivative .…”