The <i>NFATc2</i> Gene Is Involved in a Novel Cloned Translocation in a Ewing Sarcoma Variant That Couples Its Function in Immunology to Oncology

Szuhai, Károly; IJszenga, Marije; Jong, Daniëlle de; Карселадзе, А. И.; Tanke, Hans J.; Hogendoorn, Pancras C.W.

doi:10.1158/1078-0432.ccr-08-2184

Cited by 180 publications

(141 citation statements)

References 38 publications

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“…Interphase FISH on 16-mm-thick paraffin sections was performed in all 17 sporadic secondary peripheral chondrosarcomas, as described previously (Szuhai et al, 2009). The five sporadic osteochondromas used for comparison were reported previously to show homozygous deletion of EXT1 (Hameetman et al, 2007b).…”

Section: Fluorescent In Situ Hybridizationmentioning

confidence: 99%

Secondary peripheral chondrosarcoma evolving from osteochondroma as a result of outgrowth of cells with functional EXT

et al. 2011

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Secondary peripheral chondrosarcoma is the result of malignant transformation of a pre-existing osteochondroma, the most common benign bone tumor. Osteochondromas are caused by genetic abnormalities in EXT1 or EXT2: homozygous deletion of EXT1 characterizes sporadic osteochondromas (non-familial/solitary), and germline mutations in EXT1 or EXT2 combined with loss of heterozygosity define hereditary multiple osteochondromas. While cells with homozygous inactivation of EXT and wild-type cells shape osteochondromas, the cellular composition of secondary peripheral chondrosarcomas and the role of EXT in their formation have remained unclear. We report using a targeted-tiling-resolution oligo-array-CGH (array comparative genomic hybridization) that homozygous deletions of EXT1 or EXT2 are much less frequently detected (2/17, 12%) in sporadic secondary peripheral chondrosarcomas than expected based on the assumption that they originate in sporadic osteochondromas, in which homozygous inactivation of EXT1 is found in B80% of our cases. FISH with an EXT1 probe confirmed that, unlike sporadic osteochondromas, cells from sporadic secondary peripheral chondrosarcomas predominantly retained one (hemizygous deleted loci) or both copies (wild-type) of the EXT1 locus. By immunohistochemistry, we confirm the presence of cells with dysfunctional EXT1 in sporadic osteochondromas and show cells with functional EXT1 in sporadic secondary peripheral chondrosarcomas. These immuno results were verified in osteochondromas and secondary peripheral chondrosarcomas in the setting of hereditary multiple osteochondromas. Our data therefore point to a model of oncogenesis in which the osteochondroma creates a niche in which wild-type cells with functional EXT are predisposed to acquire other mutations giving rise to secondary peripheral chondrosarcoma, indicating that EXT-independent mechanisms are involved in the pathogenesis of secondary peripheral chondrosarcoma.

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Section: Fluorescent In Situ Hybridizationmentioning

confidence: 99%

Secondary peripheral chondrosarcoma evolving from osteochondroma as a result of outgrowth of cells with functional EXT

et al. 2011

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“…6 Rearrangements of EWSR1 with non-Ets family genes, including NFATc2, POU5F1, SMARCA5, ZSG and SP3, are also rare. 2,[6][7][8] ERG is also found to be involved in recurrent translocations in other tumors including prostate carcinoma and some acute myeloid leukemias. Up to 70% of prostate carcinomas harbor a translocation involving ERG and TMPRSS2, a gene located on chromosome 21q22 and encodes for an androgen dependent transmembrane protease.…”

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confidence: 99%

Expression of ERG, an Ets family transcription factor, identifies ERG-rearranged Ewing sarcoma

et al. 2012

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ERG gene encodes for an Ets family regulatory transcription factor and is involved in recurrent chromosomal translocations found in a subset of acute myeloid leukemias, prostate carcinomas and Ewing sarcomas. The purpose of this study was to examine the utility of an ERG antibody to detect EWSR1-ERG rearranged Ewing sarcomas. A formalin-fixed paraffin-embedded tissue microarray and whole-tissue sections from 32 genetically characterized Ewing sarcomas were examined: 22 with EWSR1-FLI1, 8 with EWSR1-ERG and 2 with EWSR1-NFATC2. Immunohistochemistry was performed using a rabbit anti-ERG monoclonal antibody directed against the C-terminus of the protein and a mouse anti-FLI1 monoclonal antibody against a FLI1 Ets domain (C-terminus) fusion protein. Immunoreactivity was graded for extent and intensity of positive tumor cell nuclei. ERG labeling was seen in 7/8 EWSR1-ERG cases (predominantly diffuse (5 þ ), moderate to strong), while only 3/24 non-EWR1-ERG cases showed labeling (very weak). FLI1 labeling was observed in 29/31 cases regardless of fusion variant; 23 displayed diffuse (5 þ ) strong/moderate labeling (5/7 EWSR1-ERG, 18/22 EWSR1-FLI1). Both EWSR1-NFATC2 cases had weak reactivity with FLI1 and weak or no reactivity for ERG. In conclusion, strong nuclear ERG immunoreactivity is specific for Ewing sarcomas with EWSR1-ERG rearrangement. In contrast, FLI1 was not specific to rearrangement type, likely because of cross reactivity with the highly homologous Ets DNA-binding domain present in the C-terminus of both ERG and FLI1. Modern Pathology (2012) 25, 1378-1383; doi:10.1038/modpathol.2012.97; published online 6 July 2012Keywords: Ewing sarcoma; EWSR1; ERG; FLI1; immunohistochemistry Ewing sarcoma is characterized by a recurrent translocation involving EWSR1 on 22q12. The most frequent partner is FLI1 located on 11q22, occurring in B85% of cases. 1-3 However, a minority of tumors will harbor a translocation involving EWSR1 and an alternative partner, the most common of which is ERG located on 21q12. 2-4 These characteristic translocations result in the constitutive expression of an abnormal transcription factor that is critical for Ewing sarcoma tumorigenesis, and is composed of the amino end of EWSR1, a potent transcriptional activator, and the C-terminus of FLI1/ERG that contains the Ets DNA-binding domain. Both FLI1 and ERG belong to the Ets family of transcription factors, which regulate several genes involved in cellular differentiation and growth. 2,5 Chimeric variants of EWSR1 with other Ets genes, including ETV4 and FEV, have been described but are very rare. 6 Rearrangements of EWSR1 with non-Ets family genes, including NFATc2, POU5F1, SMARCA5, ZSG and SP3, are also rare. 2,6-8

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“…22,23 In addition, a fusion between EWSR1 and a gene from a transcription factor family other than ETS, the NFATc2 gene (encodes for a member of the NFAT-transcription factor family), has recently been described. 24 In this study, cytogenetic analysis of an extraskeletal Ewing sarcoma/PNET arising in the lumbosacral region of a 5-year-old female revealed a t(4;22)(q31;q12) resulting in a novel fusion between EWSR1 and a member of the WSTF-SNF2h chromatin-remodeling complex family of genes, SMARCA5.…”

mentioning

confidence: 72%

“…[22][23][24] To date, however, there have been no reports of a fusion between EWSR1 and a chromatin-remodeling gene. In this study, we cloned the fusion gene produced by a t(4;22) (q31;q12) in an extraskeletal Ewing sarcoma/PNET and demonstrated the tumorigenic activation of SMARCA5, a gene coding for a chromatin-reorganizing protein, by chimera formation with EWSR1.…”

Section: Discussionmentioning

confidence: 99%

A novel t(4;22)(q31;q12) produces an EWSR1–SMARCA5 fusion in extraskeletal Ewing sarcoma/primitive neuroectodermal tumor

et al. 2011

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Over 90% of Ewing sarcoma/primitive neuroectodermal tumors (PNETs) feature an 11;22 translocation leading to an EWSR1-FLI1 fusion. Less commonly, a member of the ETS-transcription factor family other than FLI1 is fused with EWSR1. In this study, cytogenetic analysis of an extraskeletal Ewing sarcoma/PNET revealed a novel chromosomal translocation t(4;22)(q31;q12) as the sole anomaly. Following confirmation of an EWSR1 rearrangement by the use of EWSR1 breakpoint flanking probes, a fluorescence in situ hybridization positional cloning strategy was used to further narrow the 4q31 breakpoint. These analyses identified the breakpoint within RP11-481K16, a bacterial artificial chromosome (BAC) clone containing two gene candidates FREM and SMARCA5. Subsequent RACE, RT-PCR, and sequencing studies were conducted to further characterize the fusion transcript. An in-frame fusion of the first 7 exons of EWSR1 to the last 19 exons of SMARCA5 was identified. SMARCA5 encodes for hSNF2H, a chromatin-remodeling protein. Analogous to EWSR1-ETSexpressing NIH3T3 cells, NIH3T3 cells expressing EWSR1-hSNF2H exhibited anchorage-independent growth and formed colonies in soft agar, indicating chimeric protein tumorigenic potential. Conversely, expression of EWSR1-hSNF2H in NIH3T3 cells, unlike EWSR1-ETS fusions, did not induce EAT-2 expression. Mapping analysis demonstrated that deletion of the C-terminus (SLIDE or SANT motives) of hSNF2H impaired, and deletion of the SNF2_N domain fully abrogated NIH3T3 cell transformation by EWSR1-SMARCA5. It is proposed that EWSR1-hSNF2H may act as an oncogenic chromatin-remodeling factor and that its expression contributes to Ewing sarcoma/primitive neuroectodermal tumorigenesis. To the best of our knowledge, this is the first description of a fusion between EWSR1 and a chromatin-reorganizing gene in Ewing sarcoma/PNET and thus expands the EWSR1 functional partnership beyond transcription factor and zinc-finger gene families.

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The NFATc2 Gene Is Involved in a Novel Cloned Translocation in a Ewing Sarcoma Variant That Couples Its Function in Immunology to Oncology

Cited by 180 publications

References 38 publications

Secondary peripheral chondrosarcoma evolving from osteochondroma as a result of outgrowth of cells with functional EXT

Secondary peripheral chondrosarcoma evolving from osteochondroma as a result of outgrowth of cells with functional EXT

Expression of ERG, an Ets family transcription factor, identifies ERG-rearranged Ewing sarcoma

A novel t(4;22)(q31;q12) produces an EWSR1–SMARCA5 fusion in extraskeletal Ewing sarcoma/primitive neuroectodermal tumor

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