Molecular Detection and Targeting of EWSR1 Fusion Transcripts in Soft Tissue Tumors

Overview

Journal Med Oncol

Publisher Springer

Specialty Oncology

Date 2013 Jan 19

PMID 23329308

Citations 43

Authors

Monica Cantile

Laura Marra

Renato Franco

Paolo Ascierto

Giuseppina Liguori

Annarosaria De Chiara

Gerardo Botti

Affiliations

Soon will be listed here.

Abstract

Soft tissue tumors are a heterogeneous group of tumors, traditionally classified according to morphology and histogenesis. Molecular classification divides sarcomas into two main categories: (a) sarcomas with specific genetic alterations and (b) sarcomas showing multiple complex karyotypic abnormalities without any specific pattern. Most chromosomal alterations are represented by translocations which are increasingly detected. The identification of fusion transcripts, in fact, not only support the diagnosis but also provides the basis for the development of new therapeutic strategies aimed at blocking aberrant activity of the chimeric proteins. One of the genes most susceptible to breakage/translocation in soft tissue tumors is represented by Ewing sarcoma breakpoint region 1 (EWSR1). This gene has a large number of fusion partners, mainly associated with the pathogenesis of Ewing's sarcoma but with other soft tissue tumors too. In this review, we illustrate the characteristics of this gene/protein, both in normal cellular physiology and in carcinogenesis. We describe the different fusion partners of EWSR1, the molecular pathways in which is involved and the main molecular biology techniques for the identification of fusion transcripts and for their inhibition.

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References

Hisaoka M, Tsuji S, Morimitsu Y, Hashimoto H, Shimajiri S, Komiya S . Molecular detection of EWS-FLI1 chimeric transcripts in Ewing family tumors by nested reverse transcription-polymerase chain reaction: application to archival paraffin-embedded tumor tissues. APMIS. 1999; 107(6):577-84. DOI: 10.1111/j.1699-0463.1999.tb01595.x. View

Minoletti F, Sozzi G, Tornielli S, Pilotti S, Azzarelli A, Pierotti M . A novel EWS-ERG rearrangement generating two hybrid mRNAs in a peripheral primitive neuroectodermal tumour (pPNET) with a t(15;22) translocation. J Pathol. 1999; 186(4):434-7. DOI: 10.1002/(SICI)1096-9896(199812)186:4<434::AID-PATH199>3.0.CO;2-X. View

Antonescu C, Katabi N, Zhang L, Sung Y, Seethala R, Jordan R . EWSR1-ATF1 fusion is a novel and consistent finding in hyalinizing clear-cell carcinoma of salivary gland. Genes Chromosomes Cancer. 2011; 50(7):559-70. DOI: 10.1002/gcc.20881. View

Dal Cin P, Sciot R, Panagopoulos I, Aman P, Samson I, Mandahl N . Additional evidence of a variant translocation t(12;22) with EWS/CHOP fusion in myxoid liposarcoma: clinicopathological features. J Pathol. 1997; 182(4):437-41. DOI: 10.1002/(SICI)1096-9896(199708)182:4<437::AID-PATH882>3.0.CO;2-X. View

Prieur A, Tirode F, Cohen P, Delattre O . EWS/FLI-1 silencing and gene profiling of Ewing cells reveal downstream oncogenic pathways and a crucial role for repression of insulin-like growth factor binding protein 3. Mol Cell Biol. 2004; 24(16):7275-83. PMC: 479730. DOI: 10.1128/MCB.24.16.7275-7283.2004. View

Martini A, La Starza R, Janssen H, Bilhou-Nabera C, Corveleyn A, Somers R . Recurrent rearrangement of the Ewing's sarcoma gene, EWSR1, or its homologue, TAF15, with the transcription factor CIZ/NMP4 in acute leukemia. Cancer Res. 2002; 62(19):5408-12. View

Panagopoulos I, Hoglund M, Mertens F, Mandahl N, Mitelman F, Aman P . Fusion of the EWS and CHOP genes in myxoid liposarcoma. Oncogene. 1996; 12(3):489-94. View

Peng C, Guo W, Yang Y, Zhao H . Downregulation of SS18-SSX1 expression by small interfering RNA inhibits growth and induces apoptosis in human synovial sarcoma cell line HS-SY-II in vitro. Eur J Cancer Prev. 2008; 17(5):392-8. DOI: 10.1097/CEJ.0b013e328305a11b. View

Azuma M, Embree L, Sabaawy H, Hickstein D . Ewing sarcoma protein ewsr1 maintains mitotic integrity and proneural cell survival in the zebrafish embryo. PLoS One. 2007; 2(10):e979. PMC: 1991596. DOI: 10.1371/journal.pone.0000979. View

10.

Pellin A, Monteagudo C, Lopez-Gines C, Carda C, Boix J, Llombart-Bosch A . New type of chimeric fusion product between the EWS and ATFI genes in clear cell sarcoma (malignant melanoma of soft parts). Genes Chromosomes Cancer. 1998; 23(4):358-60. View

11.

Toub N, Bertrand J, Malvy C, Fattal E, Couvreur P . Antisense oligonucleotide nanocapsules efficiently inhibit EWS-Fli1 expression in a Ewing's sarcoma model. Oligonucleotides. 2006; 16(2):158-68. DOI: 10.1089/oli.2006.16.158. View

12.

Tannukit S, Wen X, Wang H, Paine M . TFIP11, CCNL1 and EWSR1 Protein-protein Interactions, and Their Nuclear Localization. Int J Mol Sci. 2009; 9(8):1504-1514. PMC: 2605624. DOI: 10.3390/ijms9081504. View

13.

Peter M, Couturier J, Pacquement H, Michon J, Thomas G, Magdelenat H . A new member of the ETS family fused to EWS in Ewing tumors. Oncogene. 1997; 14(10):1159-64. DOI: 10.1038/sj.onc.1200933. View

14.

Werner H, Idelman G, Rubinstein M, Pattee P, Nagalla S, Roberts Jr C . A novel EWS-WT1 gene fusion product in desmoplastic small round cell tumor is a potent transactivator of the insulin-like growth factor-I receptor (IGF-IR) gene. Cancer Lett. 2006; 247(1):84-90. DOI: 10.1016/j.canlet.2006.03.027. View

15.

Qian X, Jin L, Shearer B, Ketterling R, Jalal S, Lloyd R . Molecular diagnosis of Ewing's sarcoma/primitive neuroectodermal tumor in formalin-fixed paraffin-embedded tissues by RT-PCR and fluorescence in situ hybridization. Diagn Mol Pathol. 2005; 14(1):23-8. DOI: 10.1097/01.pdm.0000140192.27878.97. View

16.

Antonescu C, Tschernyavsky S, Woodruff J, Jungbluth A, Brennan M, Ladanyi M . Molecular diagnosis of clear cell sarcoma: detection of EWS-ATF1 and MITF-M transcripts and histopathological and ultrastructural analysis of 12 cases. J Mol Diagn. 2002; 4(1):44-52. PMC: 1906974. DOI: 10.1016/S1525-1578(10)60679-4. View

17.

Scotlandi K, Chano T, Benini S, Serra M, Manara M, Cerisano V . Identification of EWS/FLI-1 transcripts in giant-cell tumor of bone. Int J Cancer. 2000; 87(3):328-35. DOI: 10.1002/1097-0215(20000801)87:3<328::aid-ijc4>3.0.co;2-1. View

18.

Pacheco M, Horsman D, Hayes M, Clarkson P, Huwait H, Nielsen T . Small blue round cell tumor of the interosseous membrane bearing a t(2;22)(q34;q12)/EWS-CREB1 translocation: a case report. Mol Cytogenet. 2010; 3:12. PMC: 2908072. DOI: 10.1186/1755-8166-3-12. View

19.

Takenaka S, Naka N, Araki N, Hashimoto N, Ueda T, Yoshioka K . Downregulation of SS18-SSX1 expression in synovial sarcoma by small interfering RNA enhances the focal adhesion pathway and inhibits anchorage-independent growth in vitro and tumor growth in vivo. Int J Oncol. 2010; 36(4):823-31. DOI: 10.3892/ijo_00000559. View

20.

Li X, McGee-Lawrence M, Decker M, Westendorf J . The Ewing's sarcoma fusion protein, EWS-FLI, binds Runx2 and blocks osteoblast differentiation. J Cell Biochem. 2010; 111(4):933-43. PMC: 3877924. DOI: 10.1002/jcb.22782. View