title: Molecular genetic characterization of the EWS/CHN and RBP56/CHN fusion genes in extraskeletal myxoid chondrosarcoma.
abstract: Extraskeletal myxoid chondrosarcoma (EMC) is a soft-tissue neoplasm cytogenetically characterized by the translocations t(9;22)(q22;q11-12) or t(9;17)(q22;q11), generating EWS/CHN or RBP56/CHN fusion genes, respectively. In the present study, 18 EMCs were studied both cytogenetically and at the molecular level. Chromosomal aberrations were detected in 16 samples: 13 with involvement of 9q22 and 22q11-12, and three with rearrangements of 9q22 and 17q11. Fifteen cases had an EWS/CHN fusion transcript and three had an RBP56/CHN transcript. The most frequent EWS/CHN transcript (type 1; 10 tumors), involved fusion of EWS exon 12 with CHN exon 3, and the second most common (type 5; two cases) was fusion of EWS exon 13 with CHN exon 3. In all tumors with RBP56/CHN fusion, exon 6 of RBP56 was fused to exon 3 of CHN. By genomic XL PCR and sequence analyses, the breakpoints from 14 cases were mapped in the EWS, RBP56, and CHN genes. In CHN, 12 breakpoints were found in intron 2 and only two in intron 1. In EWS, the breaks occurred in introns 7 (one break), 12 (eight breaks), and 13 (one break), and in RBP56 in intron 6. Repetitive elements such as Alu and LINE sequences seem to have limited, if any, importance in the genesis of EWS/CHN and RBP56/CHN chimeras. Furthermore, there were no chi, chi-like, topoisomerase II, or translin consensus sequences in the introns harboring the translocation breakpoints, nor could the number of topo I sites in EWS, RBP56, and CHN introns explain the uneven distribution of the breakpoints among EWS or CHN introns. Additional genetic events, such as nucleotide insertions, homologies at the junction, deletions, duplications, and inversions, were found to accompany the translocations, indicating that the chromosomal translocations do not require sequence-specific recombinases or extensive homology between the recombined sequences.
authors.affiliation: Department of Clinical Genetics, Lund University Hospital, Lund, Sweden. ioannis.panagopoulos@klingen.lu.se
authors.forename: Ioannis
authors.initials: I
authors.lastname: Panagopoulos
authors.forename: Fredrik
authors.initials: F
authors.lastname: Mertens
authors.forename: Margareth
authors.initials: M
authors.lastname: Isaksson
authors.forename: Henryk A
authors.initials: HA
authors.lastname: Domanski
authors.forename: Otte
authors.initials: O
authors.lastname: Brosjö
authors.forename: Sverre
authors.initials: S
authors.lastname: Heim
authors.forename: Bodil
authors.initials: B
authors.lastname: Bjerkehagen
authors.forename: Raf
authors.initials: R
authors.lastname: Sciot
authors.forename: Paola
authors.initials: P
authors.lastname: Dal Cin
authors.forename: Jonathan A
authors.initials: JA
authors.lastname: Fletcher
authors.forename: Christopher D M
authors.initials: CD
authors.lastname: Fletcher
authors.forename: Nils
authors.initials: N
authors.lastname: Mandahl
mesh_terms: D000328:Adult; D000368:Aged; D001483:Base Sequence / Q000235:genetics; D002813:Chondrosarcoma / Q000235:genetics* / Q000473:pathology / Q000556:secondary; D019457:Chromosome Breakage / Q000235:genetics; D003001:Cloning, Molecular / Q000379:methods; D020732:Cytogenetic Analysis / Q000379:methods; D004268:DNA-Binding Proteins / Q000235:genetics*; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins / Q000235:genetics*; D015514:Oncogene Proteins, Fusion / Q000235:genetics*; D034802:RNA-Binding Protein EWS / Q000235:genetics*; D011987:Receptors, Steroid; D011988:Receptors, Thyroid Hormone; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012983:Soft Tissue Neoplasms / Q000235:genetics* / Q000473:pathology / Q000556:secondary; D035381:TATA-Binding Protein Associated Factors / Q000235:genetics*; D015534:Trans-Activators / Q000235:genetics*; D014178:Translocation, Genetic / Q000235:genetics
chemical_list: D004268:DNA-Binding Proteins; C119680:EWS-TEC fusion protein, human; C490412:NR4A3 protein, human; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D015514:Oncogene Proteins, Fusion; D034802:RNA-Binding Protein EWS; D011987:Receptors, Steroid; D011988:Receptors, Thyroid Hormone; C102041:TAF15 protein, human; D035381:TATA-Binding Protein Associated Factors; D015534:Trans-Activators