Chondrosarcoma, Extraskeletal Myxoid

Watchlist

(log in to enable)

Retrieved

2019-09-22

Source

Omim

Trials

—

Genes

NR4A3, TAF15, TFG, EWSR1, TCF12, CHN1, TEC, OSCP1, FUS, PPARG, SIX3, HDAC7, UBE2S, SGTA, TUBB3, ANO1, BCL2L11, CLDN6, SOX6, CREB3L2, TP53, ZC3H12A, SS18, SSX2, MIR106B, SMARCB1, PPARGC1A, AMHR2, RET, BCL2, CTNNB1, DDIT3, DPP4, ESRRB, HDAC1, HRAS, HSPA8, IFNA1, IFNA13, INSM1, KIT, MAP2, MCM7, MYB, MYBL1, MYC, NFATC2, PLAG1, PLAGL1, PTEN

Drugs

(-)-trans-3-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1yl)-4-(1H-indol-3-yl) pyrrolidine-2, 5-dione, (1-methyl-2-nitro-1H-imidazole-5-yl)methyl N,N'-bis(2-bromoethyl) diamidophosphate, 16-base single-stranded peptide nucleic acid oligonucleotide linked to a 7-amino acid peptide, 18-(p-(, 4-oxo-4H-chromene-2-carboxylic acid (2-(2-4-(2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-ethyl)-phenyl-2H-tetrazol-5-yl)-4,5-dimethoxy-phenyl)-amide, 7-ethyl-10-hydroxy-camptothecin, Anlotinib, Autologous CD4+ and CD8+ T cells transduced with a lentiviral vector encoding an affinity enhanced T cell receptor specific to MAGE-A4, Autologous CD4+ and CD8+ T cells transduced with lentiviral vector containing an affinity-enhanced T-cell receptor targeting the New York esophageal antigen-1, Brostallicin, Camsirubicin, Crenolanib besylate, Deforolimus, Doxorubicin hydrochloride (liposomal) ( DOXIL ), Doxorubicin(6-maleimidocaproyl)hydrazone, Fenretinide, Fibromun, Genetically modified serotype 5/3 adenovirus coding for granulocyte-macrophage colony-stimulating factor, Human/murine chimeric monoclonal antibody against endoglin, Larotrectinib ( VITRAKVI ), Mammalian target of rapamcyin (mTOR) inhibitor, N-acetylsarcosyl-glycyl-L-valyl-D-allo-isoleucyl-L-threonyl-L-norvalyl-L-isoleucyl-L-arginyl-L-prolyl-N-ethylamide, Olaratumab ( LARTRUVO ), Ombrabulin, Paclitaxel ( TAXOL ), Palifosfamide, Propranolol hydrochloride ( HEMANGEOL ), Sindbis virus envelope pseudotyped lentiviral vector encoding New York oesophageal squamous cell carcinoma-1 protein, Trabectedin ( YONDELIS ), Vinorelbine tartrate, Yttrium (90Y)-DTPA-radiolabelled chimeric monoclonal antibody against frizzled homologue 10

Interested in hearing about new therapies?

A number sign (#) is used with this entry because extraskeletal myxoid chondrosarcomas (EMCs) can be caused by somatic chromosomal translocations that result in fusion genes, most often between the NR4A3 (600542) and EWS (EWSR1; 133450) genes, but also between NR4A3 and several other genes, including RBP56 (TAF15; 601574), TCF12 (600480), and TFG (602498).

Description

Extraskeletal myxoid chondrosarcoma is a rare soft tissue neoplasm of chondroblastic origin. The tumors are most commonly found in middle-aged and elderly individuals, are more common among men, and are often detected as deep-seated lesions in the extremities. Despite their relatively low-grade malignancy, recurrence and metastasis may appear many years after the initial diagnosis. Histologic tissue section examination reveals a mixture of cellular and myxoid stromal components (Panagopoulos et al., 2002).

Clinical Features

Hisaoka et al. (2004) reported a 41-year-old Japanese man who had a local excision for EMC in his right sole at age 36 years, and amputation of the right foot because of local recurrence 2 years later. He developed metastases in the lung and popliteal fossa and died 6 years after surgery for the metastases. Histologically, the lesion was characterized by lobular configurations of short spindle or oval cells arranged in a lacelike fashion or in a loose fascicular pattern with an abundant myxoid matrix. Molecular genetics identified an NR4A3/TFG fusion gene. Hisaoka et al. (2004) used the symbol NOR1 for the NR4A3 gene.

Cytogenetics

NR4A3/EWS Fusion Gene

A recurrent t(9;22)(q22-31;q11-12) translocation was observed in EMCs by Hinrichs et al. (1985), Turc-Carel et al. (1988), Orndal et al. (1991), and Stenman et al. (1995).

In tissue derived from a skeletal myxoid chondrosarcoma that had a t(9;22)(q22-31;q11-12) translocation, Gill et al. (1995) demonstrated that the segment on chromosome 9 was fused to the N-terminal region of the EWS gene as a result of the reciprocal translocation.

Labelle et al. (1995) noted that in all known EWS fusion proteins, the RNA-recognition motif of EWS is replaced by the DNA-binding domain of the corresponding transcription factor. They demonstrated by fluorescence in situ hybridization that in 1 EMC tumor the chromosome 22 breakpoint occurred in the EWS gene. Northern blot analysis revealed an aberrant transcript that was cloned by a modified RT-PCR procedure. This transcript consisted of an in-frame fusion of the 5-prime end of EWS to the NR4A3 gene, which Labelle et al. (1995) called TEC and which has also been symbolized CSMF. This fusion transcript was detected in 6 of 8 EMCs studied, and 3 different junction types between the 2 genes were found. EWS linked to the entire NR4A3 protein. Homology analysis showed that the predicted NR4A3 protein contains a DNA-binding domain characteristic of nuclear receptors. The highest identity scores were observed with the NURR1 family of orphan nuclear receptors (NR4A2; 601828). (This situation is reminiscent of the FUS/CHOP fusion protein in which the entire CHOP (126337) protein is linked to the amino-terminal domain of FUS (137070) by an additional 26 amino acid sequence.) Labelle et al. (1995) stated that the EWS/NR4A3 gene fusion is the second example of the oncogenic conversion of a nuclear receptor in human tumorigenesis, the first being the PML/RARA gene fusion (see 180240; 102578) generated by the t(15;17) translocation in acute promyelocytic leukemia.

By cotransfection experiments of COS cells and human chondrocytes, Labelle et al. (1999) demonstrated that whereas NR4A3 moderately activates transcription from an NGFIB response element (NBRE)-containing promoter, a corresponding EWS/NR4A3 fusion protein, generated by the t(9;22) chromosomal translocation, is a highly potent transcriptional activator of the same promoter, being approximately 270-fold more active than the native receptor. EWS/NR4A3 may thus exert its oncogenic potential in chondrosarcomas by activating the transcription of target genes involved in cell proliferation.

Panagopoulos et al. (2002) found that 13 of 16 EMCs had chromosomal aberrations involving 9q22 and 22q11-q12, the sites of the NR4A3 and EWS genes, respectively, The most frequent EWS/NR4A3 fusion transcript, present in 10 tumors, involved fusion of EWS exon 12 with NR4A3 exon 3; the second most common, present in 2 cases, was fusion of EWS exon 13 with NR4A3 exon 3.

NR4A3/RBP56 Fusion Gene

Panagopoulos et al. (1999) demonstrated that RBP56 can combine with the NR4A3 gene to generate a chimeric RBP56/NR4A3 gene; the fusion gene was identified in a subset of extraskeletal myxoid chondrosarcomas with the translocation t(9;17)(q22;q11).

Panagopoulos et al. (2002) found that 3 of 16 EMCs had chromosomal rearrangements involving 9q22 and 17q11, the sites of the NR4A3 and RBP56 genes, respectively. In all tumors with RBP56/NR4A3 fusion, exon 6 of RBP56 was fused to exon 3 of NR4A3.

NR4A3/TCF12 Fusion Gene

By spectral karyotyping, Sjogren et al. (2000) identified a reciprocal t(9;15)(q22;q21) translocation in cells obtained from a tumor with characteristics of EMC. The translocation produced a chimeric transcript encoding a protein in which the first 108 amino acids of the N terminus of TCF12 (600480) were fused in-frame upstream of the entire NR4A3 sequence. The N-terminal TCF12 sequence included in the fusion product contains potential phosphorylation and N-glycosylation sites.

NR4A3/TFG Fusion Gene

Hisaoka et al. (2004) identified an NOR1/TFG fusion gene in an EMC derived from a Japanese patient. The fusion occurred between exon 6 of the TFG gene and exon 3 of the NOR1 gene.