Molecular Characterization of Dermatofibrosarcoma Protuberans

Abstract

The clinicopathologic relevance of various gene rearrangements underlying dermatofibrosarcoma protuberans (DFSP) remains insufficiently characterized. In 188 DFSPs, we determined PDGFB, COL1A1, PDGFD, COL6A3, and EMILIN2 rearrangements by fluorescence in situ hybridization (FISH). The clinicopathologic significance of rearrangement types and factors related to recurrence and metastasis were statistically analyzed. In all, classic PDGFB rearrangement, cryptic COL1A1-PDGFB fusion, and PDGFD rearrangement were identified in 172 (91.4%), 8 (4.3%), and 8 (4.3%: 4 COL6A3-PDFGD, 4 EMILIN2-PDGFD) cases, respectively. In an index DFSP harboring the cryptic fusion, the COL1A1-PDGFB transcript was confirmed by both RNA sequencing and reverse transcription-polymerase chain reaction. In comparison with cases harboring classic PDGFB rearrangement, cryptic PDGFB-rearranged DFSPs usually exhibited higher 5′-COL1A1 copy numbers. In a combined reappraisal of published and current cases, COL6A3-PDGFD-positive DFSPs (n = 16) predominated in females (n = 14, 88%) and torso (n = 14, 88%), especially the breast (n = 7, 44%); EMILIN2-PDGFD-positive DFSPs (n = 6) preferentially demonstrated near exclusively subcutaneous growth (n = 5, 83%) and fibrosarcomatous transformation (n = 5, 83%). In our cohort, local recurrence was related to fibrosarcomatous variant (P = 0.029, odds ratio = 3.478) and head and neck location (P = 0.046, odds ratio = 3.508). Distant metastasis only occurred in the fibrosarcomatous variant (9/73, 12.3%) but not in other cases. In conclusion, 8.6% of DFSPs are negative for PDGFB break-apart FISH, which, especially those with challenging subcutaneous and circumscribed manifestation, require complementary diagnosis by FISH assays targeting COL1A1 and PDGFD. The types of fusion gene rearrangements, head and neck location, and fibrosarcomatous transformation may account for clinicopathologic and prognostic variations in DFSPs and warrant future independent validation.

Platelet-Derived Growth Factor-D Fusion-Positive Dermatofibrosarcoma Protuberans: Case Report of an Atypical Breast Mass and Literature Review

“…DFSP is usually confirmed with a t(17;22) COL1A1:: PDGFB translocation via FISH in 91.4% to 96% of cases. [6][7][8][9] This fusion results in aberrant proliferation due to autocrine tyrosine kinase hyperactivity through activation of PDGFB receptor (PDGFRB) signaling. 6,14 In a study of 20 DFSP cases with a negative t(17;22) FISH, RNA-targeted NGS showed 40% (8/20) of cases were positive for a cryptic COL1A1::PDGFB fusion.…”

“…11 Thus far, COL6A3, EMILIN2, and TNC have been described as forming fusion products with PDGFD in DFSP. [7][8][9][10]12,15 Table 1 enumerates the 30 PDGFD fusionpositive cases reported in the literature, as well as the case presented here. Two of the cases in Table 1 are found in a retrospective cohort of 16 breast and upper chest DFSPs, resulting in a slight selection bias for breast tumors.…”

“…Strikingly, it has been reported that EMILIN2::PDGFD fusion-positive DFSP is strongly associated with FS transformation (5/7) relative to COL6A3::PDGFD (1/16). 9 This is especially clinically relevant, as FS-DFSP is associated with a higher recurrence rate and metastatic potential. 4,5 The single TNC::PDGFD -fusion positive DFSP reported exhibited FS transformation, but more data on other cases with this fusion are required in order to draw conclusions about the likelihood of FS change with this fusion.…”

“…In most cases (91.4%-96%), a COL1A1::PDGFB t(17;22) translocation leads to proliferation due to tyrosine kinase hyperactivity, caused by the translocated highly expressed collagen type 1 alpha 1 chain promoter (COL1A1, located on chromosome 17q21) driving unregulated autocrine platelet-derived growth factor subunit B signaling (PDGFB, located on chromosome 22q13). [6][7][8][9] Less than 10% of DFSP may be negative for the COL1A1::PDGFB fusion, and instead have an atypical fusion such as COL6A3::PDGFD t(2;11), EMILIN2:: PDGFD t(11;18), or TNC::PDGFD t(9;11). 3,[7][8][9][10][11][12] Similar to COL1A1::PDGFB, the COL6A3::PDGFD translocation brings together a different collagen gene (COL6A3, located on chromosome 2q37) and platelet-derived growth factor gene (PDGFD, located on chromosome 11q22) to drive unregulated autocrine expression of platelet-derived growth factor subunit D driven by the highly expressed collagen type IV alpha 3 chain.…”

“…[6][7][8][9] Less than 10% of DFSP may be negative for the COL1A1::PDGFB fusion, and instead have an atypical fusion such as COL6A3::PDGFD t(2;11), EMILIN2:: PDGFD t(11;18), or TNC::PDGFD t(9;11). 3,[7][8][9][10][11][12] Similar to COL1A1::PDGFB, the COL6A3::PDGFD translocation brings together a different collagen gene (COL6A3, located on chromosome 2q37) and platelet-derived growth factor gene (PDGFD, located on chromosome 11q22) to drive unregulated autocrine expression of platelet-derived growth factor subunit D driven by the highly expressed collagen type IV alpha 3 chain. Unlike PDGFB, the native PDGFD protein has an N-terminal CUB domain, which must be proteolytically cleaved at Arg-247 or Arg-249 by urokinase plasminogen activator before it can stimulate platelet-derived growth factor receptor signaling.…”