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.

TFG is a novel fusion partner of NOR1 in extraskeletal myxoid chondrosarcoma

“…This receptor protein has structural features of a ligand-activated transcription factor, such as a centrally located DNA-binding domain and a putative ligand-binding domain in the C-terminal region. The NOR1 fusion proteins in EMC are composed of the N-terminal part of EWS, TAF2N, or TCF12 fused to the entire amino acid sequence of NOR-1 (Sjö gren et al, 2000;Panagopoulos et al, 2002).…”

Extraskeletal Myxoid Chondrosarcoma: A Case Report

“…Therefore a cytogenetic study is performed. EMCS is a distinct sarcoma characterized by recurrent chromosomal translocations, typically t(9;22) (q22;q12.2), fusing EWSR1 to NR4A3 [8].…”

Extraskeletal myxoid chondrosarcoma of the thigh with a t(9;17) translocation

“…As cartilaginous areas are not common despite the name 'EMC', making a diagnosis based solely on histopathological findings is often difficult. At present, the number of reported cytogenetic studies of EMC remains small due to the rarity of the tumor (2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21). We report an additional case of EMC and review the literature on cytogenetic studies.…”