Association of EWS-FLI1 type 1 fusion with lower proliferative rate in Ewing's sarcoma

The Ewing's sarcoma (ES) family of tumors, including peripheral neuroectode rmal tumor (PNET), is defined genetically by specific chromosomal transloca tions resulting in fusion of the EWS gene with a member of the ETS family o f transcription factors, either FLI1 (90-95%) or ERG (5-10%). A second leve l of molecular genetic heterogeneity stems from the variation in the locati on of the translocation breakpoints, resulting in the inclusion of differen t combinations of exons from EWS and FLI1 (or ERG) in the fusion products. The most common type of EWS-FLI1 fusion transcript, type 1, is associated w ith a favorable prognosis and appears to encode a functionally weaker trans activator, compared to other fusion types. We sought to determine whether t he observed covariation of structure, function, and clinical course correla tes with tumor cell kinetic parameters such as proliferative rate and apopt osis, and with expression of the receptor for insulin-like growth factor I (IGF-1R), In a group of 86 ES/PNET with defined EWS-ETS fusions (45 EWS-FLI 1 type 1, 27 EWS-FLI1 non-type 1, 14 EWS-ERG), we assessed proliferation ra te by immunostaining for Ki-67 using MIB1 antibody (n = 85), apoptosis by T UNEL assay(n = 66), and IGF-1R expression by immunostaining with antibody 1 H7 (n = 78), Ki-67 proliferative index was lower in tumors with EWS-FLI1 ty pe 1 than those with non-type 1 EWS-FLI1, whether analyzed as a continuous (P = 0.049) or categorical (P = 0.047) variable. Logistic regression analys is suggests that this association was secondary to the association of type 1 EWS-FLI1 and lower IGF-1R expression (P = 0.04). Comparing EWS-FLI1 to EW S-ERG cases, Ki-67 proliferative index was higher in the latter (P = 0.01, Mann-Whitney test; P = 0.02, Fisher's exact test), but there was no signifi cant difference in IGF-1R, TUNEL results showed no significant differences between groups. Our results suggest that clinical and functional difference s between alternative forms of EWS-FLI1 are paralleled by differences in pr oliferative rate, possibly mediated by differential regulation of the IGF-1 R pathway.