VARIOUS REGIONS WITHIN THE ALPHA-HELICAL DOMAIN OF THE COL1A1 GENE ARE FUSED TO THE 2ND EXON OF THE PDGFB GENE IN DERMATOFIBROSARCOMAS AND GIANT-CELL FIBROBLASTOMAS

Dermatofibrosarcoma protuberans (DFSP) and its juvenile form, giant-ce ll fibroblastoma (GCF), are uncommon infiltrative tumors of the dermis , which present unique cytogenetic features, such as the reciprocal tr anslocation t(17;22) or, more commonly, supernumerary ring chromosomes containing sequences from chromosomes 17 and 22. We have recently sho wn that these aberrations are cytogenetic manifestations of gene fusio ns between the platelet-derived growth factor B-chain gene (PDGFB), th e cellular equivalent of the v-sis oncogene, and the collagen type I a lpha I gene (COL1A1), the major protein constituent of the extracellul ar matrix in connective tissue of skin. We now report characterization of COL1A1/PDGFB chimeric genes at the RNA and DNA sequence levels in a series of DFSPs and GCFs. All 16 tumors studied contained the COL1A1 /PDGFB gene. The location of breakpoints within COL1A1 varied greatly, but was always limited to the region encoding the alpha-helical domai n. The PDGFB segment of the chimeric transcript always starts with exo n 2, placing PDGFB under the control of the COL1A1 promoter and removi ng all known elements negatively controlling PDGFB transcription and t ranslation. Production of these aberrant transcripts in fibroblasts, t he suspected cell of origin of DFSP/GCF, likely causes autocrine stimu lation and cell proliferation. No specific function has yet been assig ned to exon 2 of PDGFB, and this exon does not encode for the mature g rowth factor. Its retention in all chimeric COL1A1/PDGFB genes suggest s that it is important for the normal processing of the PDGFB polypept ide. (C) 1998 Wiley-Liss, Inc.