Comprehensive Clinicopathological and Multiomics Characterization of Dermatofibrosarcoma Protuberans Revealed PDGFD Fusion as Distinct Molecular Subtype With Better Survival

Dermatofibrosarcoma protuberans (DFSP) is a locally aggressive superficial mesenchymal neoplasm characterized by COL1A1::PDGFB fusion. Recently, PDGFD has been identified as a less common fusion partner. However, the clinicopathological and molecular differences between PDGFD-fusion and PDGFB-fusion DFSP remain largely unknown. In this study of 363 DFSP, we found 10 cases with PDGFD fusion, including 2 with a previously undescribed partner involving the EMILIN1 gene. Multiomics analysis showed distinct transcriptomics, epigenomics, and copy number features for PDGFD-fusion DFSP versus PDGFB-fusion DFSP. PDGFD-fusion DFSP had higher PDGFD expression and virtually no PDGFB expression. Both clustered into the DFSP epigenomic cluster but formed a distinct subcluster with differential methylation affecting fibroblast migration genes. Copy number analysis revealed that PDGFD-fusion DFSP formed a distinct subgroup with a generally copy number–neutral profile and better survival than PDGFB-fusion DFSP that was dominated by amplification at translocation sites in chromosomes 17 and 22. Pooled analysis of 39 cases (incorporating 29 from the literature) revealed that PDGFD-fusion DFSP was more common in women (71.8% vs 42.4%, P < .001), occurred at a lower age (median, 37 years vs 45 years, P < .01), and had a higher chance of occurrence at the breast (25.6% vs 2.3%, P < .001). PDGFD-fusion DFSP also tended to center predominantly in the subcutis (63.6% vs 30%, P < .001), had a circumscribed border (50% vs 19.2%, P < .001), was smaller in size (3 cm vs 3.5 cm, P = .017), and had a lower mitotic count (median, 1 vs 3 per 10 high-power fields, P = .03). Overall, our study provided detailed multiomics characterization of PDGFD-fusion DFSP with significant clinicopathological and diagnostic implications.