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Genes Chromosomes and Cancer
O'Brien, K.P., Department of Molecular Medicine, Clinical Genetics Unit, Karolinska Hospital, Stockholm, Sweden
Seroussi, E., Department of Molecular Medicine, Clinical Genetics Unit, Karolinska Hospital, Stockholm, Sweden
Dal Cin, P., Centre for Human Genetics, University of Leuven, Leuven, Belgium
Sciot, R., Department of Pathology, University of Leuven, Leuven, Belgium
Mandahl, N., Department of Clinical Genetics, University Hospital, Lund, Sweden
Fletcher, J.A., Department of Pathology, Brigham and Women's Hsopital, Harvard Medical School, Boston, MA, United States
Turc-Carel, C., Lab. Genet. Chromosomique Tumeurs, CNRS URA1462, Faculté de Médecine, Nice, France
Dumanski, J.P., Department of Molecular Medicine, Clinical Genetics Unit, Karolinska Hospital, Stockholm, Sweden, Department of Molecular Medicine, Karolinska Hospital, CMM Building L8:00, S-171 76 Stockholm, Sweden
Dermatofibrosarcoma protuberans (DFSP) and its juvenile form, giant- cell fibroblastoma (GCF), are uncommon infiltrative tumors of the dermis, which present unique cytogenetic features, such as the reciprocal translocation t(17;22) or, more commonly, supernumerary ring chromosomes containing sequences from chromosomes 17 and 22. We have recently shown that these aberrations are cytogenetic manifestations of gene fusions between the platelet-derived growth factor B-chain gene (PDGFB), the cellular equivalent of the v-sis oncogene, and the collagen type 1 alpha 1 gene (COL1A1), the major protein constituent of the extracellular 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 domain. The PDGFB segment of the chimeric transcript always starts with exon 2, placing PDGFB under the control of the COL1A1 promoter and removing all known elements negatively controlling PDGFB transcription and translation. Production of these aberrant transcripts in fibroblasts, the suspected cell of origin of DFSP/GCF, likely causes autocrine stimulation and cell proliferation. No specific function has yet been assigned to exon 2 of PDGFB, and this exon does not encode for the mature growth factor. Its retention in all chimeric COL1A1/PDGFB genes suggests that it is important for the normal processing of the PDGFB polypeptide.
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Various regions within the alpha-helical domain of the COL1A1 gene are fused to the second exon of the PDGFB gene in dermatofibrosarcomas and giant- cell fibroblastomas
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O'Brien, K.P., Department of Molecular Medicine, Clinical Genetics Unit, Karolinska Hospital, Stockholm, Sweden
Seroussi, E., Department of Molecular Medicine, Clinical Genetics Unit, Karolinska Hospital, Stockholm, Sweden
Dal Cin, P., Centre for Human Genetics, University of Leuven, Leuven, Belgium
Sciot, R., Department of Pathology, University of Leuven, Leuven, Belgium
Mandahl, N., Department of Clinical Genetics, University Hospital, Lund, Sweden
Fletcher, J.A., Department of Pathology, Brigham and Women's Hsopital, Harvard Medical School, Boston, MA, United States
Turc-Carel, C., Lab. Genet. Chromosomique Tumeurs, CNRS URA1462, Faculté de Médecine, Nice, France
Dumanski, J.P., Department of Molecular Medicine, Clinical Genetics Unit, Karolinska Hospital, Stockholm, Sweden, Department of Molecular Medicine, Karolinska Hospital, CMM Building L8:00, S-171 76 Stockholm, Sweden
Various regions within the alpha-helical domain of the COL1A1 gene are fused to the second exon of the PDGFB gene in dermatofibrosarcomas and giant- cell fibroblastomas
Dermatofibrosarcoma protuberans (DFSP) and its juvenile form, giant- cell fibroblastoma (GCF), are uncommon infiltrative tumors of the dermis, which present unique cytogenetic features, such as the reciprocal translocation t(17;22) or, more commonly, supernumerary ring chromosomes containing sequences from chromosomes 17 and 22. We have recently shown that these aberrations are cytogenetic manifestations of gene fusions between the platelet-derived growth factor B-chain gene (PDGFB), the cellular equivalent of the v-sis oncogene, and the collagen type 1 alpha 1 gene (COL1A1), the major protein constituent of the extracellular 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 domain. The PDGFB segment of the chimeric transcript always starts with exon 2, placing PDGFB under the control of the COL1A1 promoter and removing all known elements negatively controlling PDGFB transcription and translation. Production of these aberrant transcripts in fibroblasts, the suspected cell of origin of DFSP/GCF, likely causes autocrine stimulation and cell proliferation. No specific function has yet been assigned to exon 2 of PDGFB, and this exon does not encode for the mature growth factor. Its retention in all chimeric COL1A1/PDGFB genes suggests that it is important for the normal processing of the PDGFB polypeptide.
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