e23558 Background: DF are locally invasive soft tissue tumors of fibroblast origin, with unpredictable course. CTTNB1 mutations are a hallmark of DF. Molecular-targeted therapies are lacking. Recently developed OncoSignal (www.philips.com/oncosignal) pathway activity tests enable quantitative measurement of activity of clinically relevant oncogenic signal transduction pathways (estrogen, progesterone & androgen receptors; PI3K, MAPK-AP1, TGFβ, Notch, Hedgehog, Wnt pathways), based on computational interpretation of expression levels of direct target genes of the pathway-associated transcription factor. Methods: OncoSignal was used to measure activity of signaling pathways on Affymetrix transcriptome data from sporadic DF (n = 128), generated before in our center (GEO database: GSE58697), and from presumably healthy fibroblasts (n = 63) derived from a number of different tissue types (public dataset GSE63626). Pathway activity was expressed on a normalized scale 0-100 (min and max pathway activity score depend on the cell/tissue type analyzed). Comparisons used Mann Whitney test. Results: Mean Notch (43.2+/-7.2 vs 11.2 +/- 5.2; p < .0001), PI3K (54.6 +/- 10.0 vs 48.1 +/- 6.6, p < .0001) and androgen receptor (AR) pathway activities (32.8 +/- 3.7 vs 21.7 +/- 2.4, p < .0001) were increased in DF compared to fibroblasts. MAPK-AP1 pathway activity was lower in DF (40.8+/-6.0 vs 70.2 +/- 9.5; p < .0001). Mean Wnt (p = 0.7), HH (p = 0.8) pathway activities were not different between DF and fibroblasts, however the range in Wnt pathway activity scores was larger in DF (median score 24.1, range 5.3-41.7) than in normal fibroblasts (median 26.0, range 14.6-33.0). Conclusions: The increased activity of Notch, PI3K pathways in DF is consistent with the mesenchymal nature. We confirm here the key role of AR pathway. The wide range of Wnt pathway expression was larger, suggesting the heterogeneity in TD biology, possibly related to the type of CTTNB1 mutations. Overall, the large inter-patient variation in pathway activities is in line with variety of TD course. We identified signaling pathways which may provide novel options for targeted drug treatment.