Ewing's sarcoma: diagnostic, prognostic, and therapeutic implications of molecular abnormalities.
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Journal: 2003/March - Journal of Clinical Pathology
ISSN: 0021-9746
PUBMED: 12560386
Abstract:
The identification of the non-random chromosome rearrangements between the EWS gene on chromosome 22q12 and members of the ETS gene family in Ewing's sarcoma, peripheral primitive neuroectodermal tumour, Askin tumour, and neuroepithelioma has been a key advance in understanding their common histogenesis and defining the Ewing's sarcoma family of tumours (ESFT). In addition to improvements in diagnosis and potentially the stratification of patients for risk, biological investigations of these gene fusions may define targets for much needed therapeutic strategies to eliminate minimal residual disease or metastatic disease. Insight into their relation with other oncogenic events in ESFT will advance risk group analysis and ultimately may improve clinical management and survival for patients with this disease.
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J Clin Pathol 56(2): 96-102
PMID: 12560386

Ewing’s sarcoma: diagnostic, prognostic, and therapeutic implications of molecular abnormalities

Correspondence to:
Dr S A Burchill, Candlelighter’s Children’s Cancer Research Laboratory, Cancer Research UK Clinical Centre, St James’s University Hospital, Beckett Street, Leeds LS9 7TF, UK;
ku.ca.sdeel@llihcrub.a.s
Correspondence to:
Dr S A Burchill, Candlelighter’s Children’s Cancer Research Laboratory, Cancer Research UK Clinical Centre, St James’s University Hospital, Beckett Street, Leeds LS9 7TF, UK;
ku.ca.sdeel@llihcrub.a.s
Accepted 2002 Aug 7.
Copyright © Copyright 2003 Journal of Clinical Pathology

Abstract

The identification of the non-random chromosome rearrangements between the EWS gene on chromosome 22q12 and members of the ETS gene family in Ewing’s sarcoma, peripheral primitive neuroectodermal tumour, Askin tumour, and neuroepithelioma has been a key advance in understanding their common histogenesis and defining the Ewing’s sarcoma family of tumours (ESFT). In addition to improvements in diagnosis and potentially the stratification of patients for risk, biological investigations of these gene fusions may define targets for much needed therapeutic strategies to eliminate minimal residual disease or metastatic disease. Insight into their relation with other oncogenic events in ESFT will advance risk group analysis and ultimately may improve clinical management and survival for patients with this disease.

Keywords: Ewing’s sarcoma, diagnosis, prognosis, treatment, translocations
Abstract

Ewing’s sarcoma is the second most common malignant bone tumour occurring in children and young adults, and accounts for 10–15% of all primary bone tumours.1 The annual incidence is approximately 0.6/million total population, and it usually occurs between the ages of 10 and 20 years. It affects 13/million 0–24 year olds each year in the UK,2 and is slightly more common in males than females (ratio, 1.5 : 1). It has been described in siblings,3,4 although this is rare and the disease does not appear to be implicated in familial cancer syndromes. Genetic influences may play some role in its aetiology because black Afro-Caribbean and Chinese populations are less frequently affected than the white population.5,4

Ewing’s sarcoma can affect any bone but the most common sites are the lower extremity (45%), followed by the pelvis (20%), upper extremity (13%), axial skeleton and ribs (13%), and face (2%).6 The femur is the most frequently affected bone, with the tumour usually arising in the midshaft. Typically, by light microscopy, the tumour consists of small round cells with regular round nuclei containing finely dispersed chromatin and inconspicuous nucleoli, and a narrow rim of clear or pale cytoplasm. Ultrastructurally, the tumour contains primitive cells with a smooth nuclear surface, scanty organelles, and cytoplasmic glycogen in pools or aggregates.

“The femur is the most frequently affected bone, with the tumour usually arising in the midshaft”

Tumours with similar histology also arise in soft tissues. These include peripheral primitive neuroectodermal tumour (pPNET), neuroepithelioma, and Askin tumour. pPNET is the second most common soft tissue malignancy in childhood, accounting for 20% of sarcomas.7 It is frequently found in the chest wall (Askin tumour), paraspinal tissues, abdominal wall, head and neck, and extremities.7,8 However, soft tissue extension is common in osseous Ewing’s sarcoma and infiltration of adjacent bone is frequent in soft tissue pPNETs, which often makes it difficult to determine the primary site of tumour origin.

The identification of the non-random t(11;22)(q24;q12) chromosome rearrangement9,10 in these aggressive malignant tumours arising in bone and soft tissue is strong evidence for their common histogenesis, and provides a valuable characteristic for their differential diagnosis from other small round cell tumours of childhood. These tumours, including Ewing’s sarcoma, pPNET, Askin tumour, and neuroepithelioma, are now collectively recognised as the Ewing’s sarcoma family of tumours (ESFT). In this review, the diagnostic, prognostic, and therapeutic power of the t(11;22)(q24;q12) translocation and other molecular abnormalities in ESFT will be reviewed.

Take home messages

Abbreviations

  • ESFT, Ewing’s sarcoma family of tumours

  • Euro EWING 99, European Ewing tumour working initiative of national groups 99

  • FISH, fluorescent in situ hybridisation

  • pPNET, peripheral primitive neuroectodermal tumour

  • RT-PCR, reverse transcriptase polymerase chain reaction

Abbreviations

REFERENCES

REFERENCES

References

  • 1. Huvos AG. Ewing’s sarcoma. In: Huvos AG, ed. Bone tumors: diagnosis, treatment and prognosis, 2nd ed. Philadelphia PA: Sanders, 1991:523–52.
  • 2. Cotterill SJ, Parker L, Malcolm AJ, et al. Incidence and survival for cancer in children and young adults in the North of England, 1968–1995: a report from the Northern Region young persons’ malignant disease registry. Br J Cancer 2000;83:397–403.
  • 3. Hutter RVP, Francis KC, Foote FW. Ewing’s sarcoma in siblings. Am J Surg 1964;107:598. [[PubMed]
  • 4. Zamora P, Garcia de Paredes ML, Gonzalez Baron M, et al. Ewing’s tumor in brothers. An unusual observation. Am J Clin Oncol 1986;9:358–60. [[PubMed]
  • 5. Joyce MJ, Harmon DC, Mankin HJ, et al. Ewing’s sarcoma in female siblings: a clinical report and review of the literature. Cancer 1984;53:1959–62. [[PubMed]
  • 6. Grier HE. The Ewing family of tumors. Ewing’s sarcoma and primitive neuroectodermal tumors. Pediatr Clin North Am 1997;44:991–1104. [[PubMed]
  • 7. Harms D. Soft tissue sarcoma in the Kiel pediatric registry. Curr Top Pathol 1995;89:31–45. [[PubMed]
  • 8. Kimber C, Michalski A, Spitz L, et al. Primitive neuroectodermal tumours: anatomic location, extent of surgery, and outcome. J Pediatr Surg 1998;33:39–41. [[PubMed]
  • 9. Aurias A, Rimbaut C, Buffe D, et al. Translocation involving chromosome 22 in Ewing’s sarcoma. A cytogenetic study of four fresh tumors. Cancer Genet Cytogenet 1984;12:21–5. [[PubMed]
  • 10. Turc-Carel C, Philip I, Berger MP, et al. Chromosome study of Ewing’s sarcoma (ES) cell lines. Consistency of a reciprocal translocation t(11;22)(q24;q12). Cancer Genet Cytogenet 1984;12:1–19. [[PubMed]
  • 11. May WA, Lessnick SL, Braun BS, et al. The Ewing’s sarcoma EWS/FLI-1 fusion gene encodes a more potent transcriptional activator and is a more powerful transforming gene than FLI-1. Mol Cell Biol 1993;13:7393–8.
  • 12. Ohno T, Rao VN, Reddy ES. EWS/Fli-1 chimeric protein is a transcriptional activator. Cancer Res 1993;53:5859–63. [[PubMed]
  • 13. Chan JHC. Molecular analysis of primitive neuroectodermal tumors: a new model for the study of solid tumors showing specific chromosomal translocations. Adv Anat Pathol 1994;1:87. [PubMed]
  • 14. Sorensen PH, Triche TJ. Gene fusions encoding chimaeric transcription factors in solid tumours. Semin Cancer Biol 1996;7:3–14. [[PubMed]
  • 15. Urano F, Umezawa A, Hong W, et al. A novel chimera gene between EWS and EIA-F, encoding the adenovirus enhancing-binding protein, in extraosseous Ewing’s sarcoma. Biochem Biophys Res Commun 1996;219:608–12. [[PubMed]
  • 16. Peter M, Couturier J, Pacquement H, et al. A new member of the ETS family fused to EWS in Ewing’s tumors. Oncogene 1997;14:1159–64. [[PubMed]
  • 17. Batanian JR, Bridge JA, Wickert R, et al. EWS/FLI-1 fusion signal inserted into chromosome 11 in one patient with morphologic features of Ewing sarcoma, but lacking t(11;22). Cancer Genet Cytogenet 2002;133:72–5. [[PubMed]
  • 18. Peter M, Gilbert E, Delattre O. A multiplex real-time PCR assay for the detection of gene fusions observed in solid tumors. Lab Invest 2001;81:905–912. [[PubMed]
  • 19. Desmaze C, Zucman J, Delattre O, et al. Unicolor and bicolour in situ hybridization in the diagnosis of peripheral neuroepithelioma and related tumors. Genes Chromosomes Cancer 1992;5:30–4. [[PubMed]
  • 20. Taylor C, Patel K, Jones T, et al. Diagnosis of Ewing’s sarcoma and peripheral neuroectodermal tumour based on the detection of t(11;22) using fluorescence in situ hybridisation. Br J Cancer 1993;67:128–33.
  • 21. McManus AP, Gusterson BA, Pinkerton CR, et al. Diagnosis of Ewing’s sarcoma and related tumours by detection of chromosome 22q12 translocations using fluorescence in situ hybridization on tumour touch imprints. J Pathol 1995;176:137–42. [[PubMed]
  • 22. Sorensen PHB, Shimada H, Liu XF, et al. Biphenotypic sarcomas with myogenic and neural differentiation express the Ewing’s sarcoma EWS/FLI1 fusion gene. Cancer Res 1995;55:1385–92. [[PubMed]
  • 23. Tan S-Y, Burchill S, Brownhill SC, et al. Small round cell tumour with biphenotypic differentiation and variant of t(21;22)(q22;q12). Pediatr Dev Pathol 2001;4:391–6. [[PubMed]
  • 24. Thorner P, Squire J, Chilton-MacNeil S, et al. Is the EWS–FLI-1 fusion transcript specific for Ewing sarcoma and peripheral primitive neuroectodermal tumor? A report of four cases showing this transcript in a wider range of tumor types. Am J Pathol 1996;148:1125–38.
  • 25. Burchill SA, Wheeldon J, Cullinane C, et al. EWS–FLI1 fusion transcripts identified in patients with typical neuroblastoma. Eur J Cancer 1997;33:239–43. [[PubMed]
  • 26. Mastik MF, Molenaar WM, Boudewijn E, et al. Translocation (11;22)(q24;q12) in a small cell tumor of the thigh in a two-year-old boy: immunohistology, cytogenetics, molecular genetics, and review of the literature. Hum Pathol 1999;30:352–5. [[PubMed]
  • 27. Sainati L, Scapinello A, Montaldi A, et al. A mesenchymal chondrosarcoma of a child with the reciprocal translocation (11; 22)(q24;q12). Cancer Genet Cytogenet 1993;71:144–7. [[PubMed]
  • 28. Maitra A, Weinberg AG, Schneider N, et al. Detection of the t(11;22)(q24;q12) translocation and EWS–FLI1 fusion transcript in a case of solid pseudopapillary tumor of the pancreas. Pediatr Dev Pathol 2000;3:603–5. [[PubMed]
  • 29. de Alava E. Transcripts, transcripts everywhere. Adv Anat Pathol 2001;8:264–72. [[PubMed]
  • 30. Zoubek A, Dockhorn-Dworniczak B, Delattre O, et al. Does expression of different EWS chimeric transcripts define clinically distinct risk groups of Ewing tumor patients? J Clin Oncol 1996;14:1245–51. [[PubMed]
  • 31. de Alava E, Kawai A, Healey JH, et al. EWS–FLI1 fusion transcript structure is an independent determinant of prognosis in Ewing’s sarcoma. J Clin Oncol 1998;16:1248–55. [[PubMed]
  • 32. Lin PP, Brody RI, Hamelin AC, et al. Differential transactivation by alternative EWS–FLI1 fusion proteins correlates with clinical heterogeneity in Ewing’s sarcoma. Cancer Res 1999;59:1428–14. [[PubMed]
  • 33. de Alava E, Panizo A, Antonescu CR, et al. Association of EWS–FLI1 type 1 fusion with lower proliferative rate in Ewing’s sarcoma. Am J Pathol 2000;156:849–55.
  • 34. Ginsberg JP, de Alava E, Ladanyi M, et al. EWS–FLI1 and EWS–ERG gene fusions are associated with similar clinical phenotypes in Ewing’s sarcoma. J Clin Oncol 1999;17:1809–14. [[PubMed]
  • 35. Peter M, Magdelenat H, Michon J, et al. Sensitive detection of occult Ewing’s cells by the reverse transcriptase-polymerase chain reaction. Br J Cancer 1995;72:96–100.
  • 36. West DC, Grier HE, Swallow MM, et al. Detection of circulating tumor cells in patients with Ewing’s sarcoma and peripheral primitive neuroectodermal tumor. J Clin Oncol 1997;15:583–8. [[PubMed]
  • 37. de Alava E, Lozano MD, Patino A, et al. Ewing family tumours: potential prognostic value of reverse-transcriptase polymerase chain reaction detection of minimal residual disease in peripheral blood samples. Diagn Mol Pathol 1998;7:152–7. [[PubMed]
  • 38. Pfleiderer C, Zoubek A, Gruber B, et al. Detection of tumour cells in peripheral blood and bone marrow from Ewing tumour patients by RT-PCR. Int J Cancer 1995;64:135–9. [[PubMed]
  • 39. Toretsky JA, Neckers L, Wexler LH. Detection of (11;22)(q24;q12) translocation-bearing cells in peripheral blood progenitor cells of patients with Ewing’s sarcoma family of tumors. J Natl Cancer Inst 1995;87:385–6. [[PubMed]
  • 40. Zoubek A, Ladenstein R, Windhager R, et al. Predictive potential of testing for bone marrow involvement in Ewing tumor patients by RT-PCR: a preliminary evaluation. Int J Cancer 1998;79:56–60. [[PubMed]
  • 41. Fagnou C, Michon J, Peter M, et al. Presence of tumor cells in bone marrow but not in blood is associated with adverse prognosis in patients with Ewing’s tumor. J Clin Oncol 1998;16:1707–11. [[PubMed]
  • 42. Mugneret F, Lizard S, Aurias A, et al. Chromosomes in Ewing’s sarcoma. II. Nonrandom additional changes, trisomy 8 and der(16)t(1;16). Cancer Genet Cytogenet 1988;32:239–45. [[PubMed]
  • 43. Armengol G, Tarkkanen M, Virolainen M, et al. Recurrent gains of 1q, 8 and 12 in the Ewing family of tumours by comparative genomic hybridisation. Br J Cancer 1997;75:1403–9.
  • 44. Maurici D, Perez-Atayde A, Grier HE, et al. Frequency and implications of chromosome 8 and 12 gains in Ewing sarcoma. Cancer Genet Cytogenet 1998;100:106–10. [[PubMed]
  • 45. Tarkkanen M, Kiuru-Kuhlefelt S, Blomqvist C, et al. Clinical correlations of genetic changes by comparative genomic hybridization in Ewing sarcoma and related tumors. Cancer Genet Cytogenet 1999;114:35–41. [[PubMed]
  • 46. Zielenska M, Zhang ZM, Ng K, et al. Acquisition of secondary structural chromosomal changes in pediatric Ewing sarcoma is a probable prognostic factor for tumor response and clinical outcome. Cancer 2001;91:2156–64. [[PubMed]
  • 47. Douglass EC, Rowe ST, Valentine M, et al. A second nonrandom translocation, der(16)t(1;16)(q21;q13), in Ewing sarcoma and peripheral neuroectodermal tumor. Cytogenet Cell Genet 1990;53:87–90. [[PubMed]
  • 48. Hattinger CM, Rumpler S, Strehl S, et al. Prognostic impact of deletions at 1p36 and numerical aberrations in Ewing tumors. Genes Chromosomes Cancer 1999;24:243–54. [[PubMed]
  • 49. Kullendorff CM, Mertens F, Donner M, et al. Cytogenetic aberrations in Ewing sarcoma: are secondary changes associated with clinical outcome? Med Pediatr Oncol 1999;32:79–83. [[PubMed]
  • 50. Kovar H, Jug G, Aryee DN, et al. Among genes involved in the RB dependent cell cycle regulatory cascade, the p16 tumor suppressor gene is frequently lost in the Ewing family of tumors. Oncogene 1997;15:2225–32. [[PubMed]
  • 51. Lopez-Guerrero JA, Pellin A, Noguers R, et al. Molecular analysis of the 9p21 locus and p53 genes in Ewing family tumors. Lab Invest 2001;81:803–14. [[PubMed]
  • 52. Maitra A, Roberts H, Weinberg AG, et al. Aberrant expression of tumor suppressor proteins in the Ewing family of tumors. Arch Pathol Lab Med 2001;125:1207–12. [[PubMed]
  • 53. Matsumoto Y, Tanaka K, Nakatani F, et al. Downregulation and forced expression of EWS–FLI1 fusion gene results in changes in the expression of G(1) regulatory genes. Br J Cancer 2001;23:768–75.
  • 54. Wei G, Antonescu CR, de Alava E, et al. Prognostic impact of INK4A deletion in Ewing sarcoma. Cancer 2000;89:793–9. [[PubMed]
  • 55. Park YK, Chi SG, Kim YW, et al. Mutational alteration of the p16CDKN2a tumor suppressor gene is infrequent in Ewing’s sarcoma. Oncol Rep 1999;6:1261–6. [[PubMed]
  • 56. Quelle DE, Cheng M, Ashmun RA, et al. Cancer-associated mutations at the INK4a locus cancel cell cycle arrest by p16INK4a but not by the alternative reading frame protein p19ARF. Proc Natl Acad Sci U S A 1997;94:669–73.
  • 57. Vonlanthen S, Heighway J, Tschan MP, et al. Expression of p16INK4a/p16alpha and p19ARF/p16beta is frequently altered in non-small cell lung cancer and correlates with p53 overexpression. Oncogene 1998;17:2779–85. [[PubMed]
  • 58. Kovar H, Auinger A, Jug G, et al. Narrow spectrum of infrequent p53 mutations and absence of MDM2 amplification in Ewing tumours. Oncogene 1993;8:2683–90. [[PubMed]
  • 59. Hamelin R, Zucman J, Melot T, et al. p53 mutations in human tumors with chimeric EWS/FLI-1 genes. Int J Cancer 1994;57:336–40. [[PubMed]
  • 60. Wadayama B, Toguchida J, Yamaguchi T, et al. P53 expression and its relationship to DNA alterations in bone and soft tissue sarcomas. Br J Cancer 1993;68:1134–9.
  • 61. Radig K, Schneider-Stock R, Rose I, et al. p53 and ras mutations in Ewing’s sarcoma. Pathol Res Pract 1998;194:157–62. [[PubMed]
  • 62. de Alava E, Antonescu CR, Panizo A, et al. Prognostic impact of p53 status in Ewing sarcoma. Cancer 2000;89:783–92. [[PubMed]
  • 63. Abudu A, Mangham DC, Reynolds GM, et al. Overexpression of the p53 protein in primary Ewing’s sarcoma of bone: relationship to tumour stage, response and prognosis. Br J Cancer 1999;79:1185–9.
  • 64. Maeda T, Nishimura N, Nakamura H, et al. p21 (WAF1/Cip1/Sdi1/Pic1) mRNA is expressed in neuroblastoma cell lines but not in Ewing’s sarcoma and primitive neuroectodermal tumor cell lines. Acta Paediatr Jpn 1997;39:590–4. [[PubMed]
  • 65. Jiang M, Shao ZM, Wu J, et al. p21/waf1/cip1 and mdm-2 expression in breast carcinoma patients as related to prognosis. Int J Cancer 1997;74:529–34. [[PubMed]
  • 66. Gomyo Y, Ideda M, Osaki M, et al. Expression of p21 (waf1/cip1/sdi1), but not p53 protein, is a factor in the survival of patients with advanced gastric carcinoma. Cancer 1997;79:2067–72. [[PubMed]
  • 67. Stein JP, Ginsberg DA, Grossfeld GD, et al. Effect of p21WAF1/CIP1 expression on tumor progression in bladder cancer. J Natl Cancer Inst 1998;90:1072–9. [[PubMed]
  • 68. Kovar H, Aryee DN, Jug G, et al. EWS/FLI-1 antagonists induce growth inhibition of Ewing tumor cells in vitro. Cell Growth Differ 1996;7:429–37. [[PubMed]
  • 69. Tanaka K, Iwakuma T, Harimaya K, et al. EWS–Fli1 antisense ligodeoxynucleotide inhibits proliferation of human Ewing’s sarcoma and primitive neuroectodermal tumor cells. J Clin Invest 1997;99:239–47.
  • 70. Dohjima T, Ohno T, Banno Y, et al. Preferential down-regulation of phospholipase C-beta in Ewing’s sarcoma cells transfected with antisense EWS–Fli-1. Br J Cancer 2000;82:16–19.
  • 71. Lambert G, Bertrand JR, Fattal E, et al. EWS fli-1 antisense nanocapsules inhibits Ewing sarcoma-related tumor in mice. Biochem Biophys Res Commun 2000;279:401–6. [[PubMed]
  • 72. Bailly RA, Bosselut R, Zucman J, et al. DNA-binding and transcriptional activation properties of the EWS–FLI-1 fusion protein resulting from the t(11;22) translocation in Ewing sarcoma. Mol Cell Biol 1994;14:3230–41.
  • 73. Mao X, Miesfeldt S, Yang H, et al. The FLI-1 and chimeric EWS–FLI-1 oncoproteins display similar DNA binding specificities. J Biol Chem 1994;269:18216–22. [[PubMed]
  • 74. Thompson AD, Braun BS, Arvand A, et al. EAT-2 is a novel SH2 domain containing protein that is up regulated by Ewing’s sarcoma EWS/FLI1 fusion gene. Oncogene 1996;13:2649–58. [[PubMed]
  • 75. Arvand A, Denny CT. Biology of EWS/ETS fusions in Ewing’s family tumors. Oncogene 2001;20:5747–54. [[PubMed]
  • 76. Wang M, Xie Y, Girnita L, et al. Regulatory role of mevalonate and N-linked glycosylation in proliferation and expression of the EWS/FLI-1 fusion protein in Ewing’s sarcoma cells. Exp Cell Res 1999;246:38–46. [[PubMed]
  • 77. Yi H, Fujimura Y, Ouchida M, et al. Inhibition of apoptosis by normal and aberrant Fli-1 and erg proteins involved in human solid tumors and leukemias. Oncogene 1997;14:1259–68. [[PubMed]
  • 78. Fredericks WJ, Ayyanathan K, Rauscher FJ, 3rd. Regulating the neoplastic phenotype using engineered transcriptional repressors. Cancer Lett 2001;162(suppl):S23–32. [[PubMed]
  • 79. Fredericks WJ, Ayyanathan K, Herlyn M, et al. An engineered PAX3–KRAB transcriptional repressor inhibits the malignant phenotype of alveolar rhabdomyosarcoma cells harboring the endogenous PAX3–FKHR oncogene. Mol Cell Biol 2000;20:5019–31.
  • 80. Bosilevac JM, Olsen RJ, Bridge JA, et al. Tumor cell viability in clear cell sarcoma requires DNA binding activity of the EWS/ATF1 fusion protein. J Biol Chem 1999;274:34811–18. [[PubMed]
  • 81. May WA, Arvand A, Thompson AD, et al. EWS/FLI1-induced manic fringe renders NIH 3T3 cells tumorigenic. Nat Genet 1997;17:495–7. [[PubMed]
  • 82. Braun BS, Frieden R Lessnick SL, et al. Identification of target genes for the Ewing’s sarcoma EWS/FLI fusion protein by representational difference analysis. Mol Cell Biol 1995;15:4623–30.
  • 83. Arvand A, Bastians H, Welford SM, et al. EWS/FLI1 up regulates mE2-C, a cyclin-selective ubiquitin conjugating enzyme involved in cyclin B destruction. Oncogene 1998;17:2039–45. [[PubMed]
  • 84. Hahm KB, Cho K, Lee C. Repression of the gene encoding the TGF-beta type II of the EWS–FLI-1 oncoprotein. Nat Genet 1999;23:222–7. [[PubMed]
  • 85. Im YH, Kim HT, Lee C, et al. EWS–FLI1, EWS–ERG, and EWS–ETV1 oncoproteins of Ewing tumor family all suppress transcription of transforming growth factor beta type II receptor gene. Cancer Res 2000;60:1536–40. [[PubMed]
  • 86. Zwerner JP, May WA. PDGF-C is an EWS/FLI induced transforming growth factor in Ewing family tumors. Oncogene 2001;20:626–33.
  • 87. Massuda ES, Dunphy EJ, Redman RA, et al. Regulated expression of the diphtheria toxin A chain by a tumor-specific chimeric transcription factor results in selective toxicity for alveolar rhabdomyosarcoma cells. Proc Natl Acad Sci U S A 1997;94:14701–6.
  • 88. Yang L, Chansky HA, Hickstein DD. EWS–Fli-1 fusion protein interacts with hyperphosphorylated RNA polymerase II and interferes with serine-arginine protein-mediated RNA splicing. J Biol Chem 2000;275:37612–18. [[PubMed]
  • 89. Yang L, Embree LJ, Hickstein DD. TLS-ERG leukaemia fusion protein inhibits RNA splicing mediated by serine-arginine proteins. Mol Cell Biol 2000;20:3345–54.
  • 90. Knoop LL, Baker SJ. EWS/FLI1 alters 5′-splice site selection. J Biol Chem 2001;276:22317–22. [[PubMed]
  • 91. Jaishankar S, Zhang J, Roussel MF, Baker SJ. Transforming activity of EWS/FLI is not strictly dependent upon DNA-binding activity. Oncogene 1999;18:5592–7. [[PubMed]
  • 92. Mackall C, Berzofsky J, Helman LJ. Targeting tumor specific translocations in sarcomas in pediatric patients for immunotherapy. Clin Orthop 2000;373:25–31. [[PubMed]
  • 93. Worley BS, van den Broeke LT, Goletz TJ, et al. Antigenicity of fusion proteins from sarcoma-associated chromosomal translocations. Cancer Res 2001;61:6868–75. [[PubMed]
  • 94. Linehan DC, Bowne WB, Lewis JJ. Immunotherapeutic approaches to sarcoma. Semin Surg Oncol 1999;17:72–7. [[PubMed]
  • 95. Maki RG. Soft tissue sarcoma as a model disease to examine cancer immunotherapy. Curr Opin Oncol 2001;13:270–4. [[PubMed]
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