Seminars in Oncology
Volume 36, Issue 4 , Pages 312-323 , August 2009

Translocation-Related Sarcomas

  • Fredrik Mertens

      Affiliations

    • Department of Clinical Genetics, Lund University Hospital, Lund, Sweden
    • These authors contributed equally to this work.
  • ,
  • Cristina R. Antonescu

      Affiliations

    • Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, NY
    • These authors contributed equally to this work.
  • ,
  • Peter Hohenberger

      Affiliations

    • Division of Surgical Oncology and Thoracic Surgery, Department of Surgery, University Hospital Mannheim, Mannheim, Germany
    • These authors contributed equally to this work.
  • ,
  • Marc Ladanyi

      Affiliations

    • Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, NY
    • These authors contributed equally to this work.
  • ,
  • Piergiorgio Modena

      Affiliations

    • Unit of Molecular Cytogenetics, Fondazione IRCCS, Istituto Nazionale dei Tumori, Milan, Italy
    • These authors contributed equally to this work.
  • ,
  • Maurizio D'Incalci

      Affiliations

    • Department of Oncology, Mario Negri Institute, Milan, Italy
    • These authors contributed equally to this work.
  • ,
  • Paolo G. Casali

      Affiliations

    • Istituto Nazionale Tumori, Milan, Italy
    • These authors contributed equally to this work.
  • ,
  • Massimo Aglietta

      Affiliations

    • University of Torino-Ospedale Mauriziano, IRCC, Candiolo, Italy
    • These authors contributed equally to this work.
  • ,
  • Thor Alvegård

      Affiliations

    • Department of Cancer Epidemiology, University Hospital, Lund, Sweden
    • These authors contributed equally to this work.
    • Corresponding Author InformationAddress correspondence to Thor Alvegård, MD, PhD, University Hospital, Department of Cancer Epidemiology, Lund S-221-85, Sweden

References 

  1. Mitelman F, Johansson B and Mertens F, editors. Mitelman Database of Chromosome Aberrations in Cancer (2009). http://cgap.nci.nih.gov/Chromosomes/Mitelman.
  2. Mitelman F, Johansson B, Mertens F. The impact of translocations and gene fusions on cancer causation. Nat Rev Cancer. 2007;7:233–245
  3. Mitelman F, Johansson B, Mertens F. Fusion genes and rearranged genes as a linear function of chromosome aberrations in cancer. Nat Genet. 2004;36:331–334
  4. Helman LJ, Meltzer P. Mechanisms of sarcoma development. Nat Rev Cancer. 2003;3:685–694
  5. Tomlins SA, Rhodes DR, Perner S, Dhanasekaran SM, Mehra R, Sun XW, et al. Recurrent fusion of TMPRSS2 and ETS transcription factor genes in prostate cancer. Science. 2005;310:644–648
  6. Fletcher CDM, Unni KK, Mertens F. World Health Organization classification of tumours (Pathology and genetics of tumours of soft tissue and bone). In: Lyon, France: IARC Press; 2002;p. 427
  7. Abrams TA, Schuetze SM. Targeted therapy for dermatofibrosarcoma protuberans. Curr Oncol Rep. 2006;8:291–296
  8. Ley TJ, Mardis ER, Ding L, Fulton B, McLellan MD, Chen K, et al. DNA sequencing of a cytogenetically normal acute myeloid leukaemia genome. Nature. 2008;456:66–72
  9. Greaves MF, Wiemels J. Origins of chromosome translocations in childhood leukaemia. Nat Rev Cancer. 2003;3:639–649
  10. Sorensen PH, Lynch JC, Qualman SJ, Tirabosco R, Lim JF, Maurer HM, et al. PAX3-FKHR and PAX7-FKHR gene fusions are prognostic indicators in alveolar rhabdomyosarcoma: a report from the Children's Oncology Group. J Clin Oncol. 2002;20:2672–2679
  11. Stegmaier K, Wong JS, Ross KN, Chow KT, Peck D, Wright RD, et al. Signature-based small molecule screening identifies cytosine arabinoside as an EWS/FLI modulator in Ewing sarcoma. PLoS Med. 2007;4:e122
  12. Martins AS, Ordonez JL, Garcia-Sanchez A, Herrero D, Sevillano V, Osuna D, et al. A pivotal role for heat shock protein 90 in Ewing sarcoma resistance to anti-insulin-like growth factor 1 receptor treatment: in vitro and in vivo study. Cancer Res. 2008;68:6260–6270
  13. Lesko E, Gozdzik J, Kijowski J, Jenner B, Wiecha O, Majka M. HSP90 antagonist, geldanamycin, inhibits proliferation, induces apoptosis and blocks migration of rhabdomyosarcoma cells in vitro and seeding into bone marrow in vivo. Anticancer Drugs. 2007;18:1173–1181
  14. Bauer S, Yu LK, Demetri GD, Fletcher JA. Heat shock protein 90 inhibition in imatinib-resistant gastrointestinal stromal tumor. Cancer Res. 2006;66:9153–9161
  15. Tsuda M, Davis IJ, Argani P, Shukla N, McGill GG, Nagai M, et al. TFE3 fusions activate MET signaling by transcriptional upregulation, defining another class of tumors as candidates for therapeutic MET inhibition. Cancer Res. 2007;67:919–929
  16. Gardner K, Leahy M, Alvarez-Gutierrez M, Jusdon I, Scurr M. Activity of the VEGFR/KIT tyrosine kinase inhibitor cediranib (AZD2171) in alveolar soft part sarcoma [abstract]. Proc Connective Tissue Oncol Soc. 2008;14:34936
  17. Delattre O, Zucman J, Melot T, Garau XS, Zucker JM, Lenoir GM, et al. The Ewing family of tumors—a subgroup of small-round-cell tumors defined by specific chimeric transcripts. N Engl J Med. 1994;331:294–299
  18. Arvand A, Denny CT. Biology of EWS/ETS fusions in Ewing's family tumors. Oncogene. 2001;20:5747–5754
  19. Zucman J, Melot T, Desmaze C, Ghysdael J, Plougastel B, Peter M, et al. Combinatorial generation of variable fusion proteins in the Ewing family of tumours. EMBO J. 1993;12:4481–4487
  20. Plougastel B, Zucman J, Peter M, Thomas G, Delattre O. Genomic structure of the EWS gene and its relationship to EWSR1, a site of tumor-associated chromosome translocation. Genomics. 1993;18:609–615
  21. Zoubek A, Dockhorn-Dworniczak B, Delattre O, Christiansen H, Niggli F, Gatterer-Menz I, et al. Does expression of different EWS chimeric transcripts define clinically distinct risk groups of Ewing tumor patients?. J Clin Oncol. 1996;14:1245–1251
  22. Aryee DN, Sommergruber W, Muehlbacher K, Dockhorn-Dworniczak B, Zoubek A, Kovar H. Variability in gene expression patterns of Ewing tumor cell lines differing in EWS-FLI1 fusion type. Lab Invest. 2000;80:1833–1844
  23. de Alava E, Kawai A, Healey JH, Fligman I, Meyers PA, Huvos AG, et al. EWS-FLI1 fusion transcript structure is an independent determinant of prognosis in Ewing's sarcoma. J Clin Oncol. 1998;16:1248–1255
  24. Ginsberg JP, de Alava E, Ladanyi M, Wexler LH, Kovar H, Paulussen M, et al. EWS-FLI1 and EWS-ERG gene fusions are associated with similar clinical phenotypes in Ewing's sarcoma. J Clin Oncol. 1999;17:1809–1814
  25. Kovar H, Jug G, Aryee DN, Zoubek A, Ambros P, Gruber B, 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;15:2225–2232
  26. Huang HY, Illei PB, Zhao Z, Mazumdar M, Huvos AG, Healey JH, et al. Ewing sarcomas with p53 mutation or p16/p14ARF homozygous deletion: a highly lethal subset associated with poor chemoresponse. J Clin Oncol. 2005;23:548–558
  27. Grier HE, Krailo MD, Tarbell NJ, Link MP, Fryer CJ, Pritchard DJ, et al. Addition of ifosfamide and etoposide to standard chemotherapy for Ewing's sarcoma and primitive neuroectodermal tumor of bone. N Engl J Med. 2003;348:694–701
  28. Wagner LM, McAllister N, Goldsby RE, Rausen AR, McNall-Knapp RY, McCarville MB, et al. Temozolomide and intravenous irinotecan for treatment of advanced Ewing sarcoma. Pediatr Blood Cancer. 2007;48:132–139
  29. Haldar M, Hancock JD, Coffin CM, Lessnick SL, Capecchi MR. A conditional mouse model of synovial sarcoma: insights into a myogenic origin. Cancer Cell. 2007;11:375–388
  30. Rosen G, Forscher C, Lowenbraun S, Eilber F, Eckardt J, Holmes C, et al. Synovial sarcoma (Uniform response of metastases to high dose ifosfamide). Cancer. 1994;73:2506–2511
  31. Davis RJ, D'Cruz CM, Lovell MA, Biegel JA, Barr FG. Fusion of PAX7 to FKHR by the variant t(1;13)(p36;q14) translocation in alveolar rhabdomyosarcoma. Cancer Res. 1994;54:2869–2872
  32. Galili N, Davis RJ, Fredericks WJ, Mukhopadhyay S, Rauscher FJ, Emanuel BS, et al. Fusion of a fork head domain gene to PAX3 in the solid tumour alveolar rhabdomyosarcoma. Nat Genet. 1993;5:230–235
  33. Barr FG, Qualman SJ, Macris MH, Melnyk N, Lawlor ER, Strzelecki DM, et al. Genetic heterogeneity in the alveolar rhabdomyosarcoma subset without typical gene fusions. Cancer Res. 2002;62:4704–4710
  34. Kelly KM, Womer RB, Sorensen PH, Xiong QB, Barr FG. Common and variant gene fusions predict distinct clinical phenotypes in rhabdomyosarcoma. J Clin Oncol. 1997;15:1831–1836
  35. Anderson J, Gordon T, McManus A, Mapp T, Gould S, Kelsey A, et al. Detection of the PAX3-FKHR fusion gene in paediatric rhabdomyosarcoma: a reproducible predictor of outcome?. Br J Cancer. 2001;85:831–835
  36. Bridge JA, Liu J, Qualman SJ, Suijkerbuijk R, Wenger G, Zhang J, et al. Genomic gains and losses are similar in genetic and histologic subsets of rhabdomyosarcoma, whereas amplification predominates in embryonal with anaplasia and alveolar subtypes. Genes Chromosomes Cancer. 2002;33:310–321
  37. Crist WM, Anderson JR, Meza JL, Fryer C, Raney RB, Ruymann FB, et al. Intergroup rhabdomyosarcoma study-IV: results for patients with nonmetastatic disease. J Clin Oncol. 2001;19:3091–3102
  38. Bomgaars LR, Bernstein M, Krailo M, Kadota R, Das S, Chen Z, et al. Phase II trial of irinotecan in children with refractory solid tumors: a Children's Oncology Group study. J Clin Oncol. 2007;25:4622–4627
  39. Vassal G, Couanet D, Stockdale E, Geoffray A, Geoerger B, Orbach D, et al. Phase II trial of irinotecan in children with relapsed or refractory rhabdomyosarcoma: a joint study of the French Society of Pediatric Oncology and the United Kingdom Children's Cancer Study Group. J Clin Oncol. 2007;25:356–361
  40. Bisogno G, Riccardi R, Ruggiero A, Arcamone G, Prete A, Surico G, et al. Phase II study of a protracted irinotecan schedule in children with refractory or recurrent soft tissue sarcoma. Cancer. 2006;106:703–707
  41. Sreekantaiah C, Karakousis CP, Leong SP, Sandberg AA. Cytogenetic findings in liposarcoma correlate with histopathologic subtypes. Cancer. 1992;69:2484–2495
  42. Aman P, Ron D, Mandahl N, Fioretos T, Heim S, Arheden K, et al. Rearrangement of the transcription factor gene CHOP in myxoid liposarcomas with t(12;16)(q13;p11). Genes Chromosomes Cancer. 1992;5:278–285
  43. Crozat A, Aman P, Mandahl N, Ron D. Fusion of CHOP to a novel RNA-binding protein in human myxoid liposarcoma. Nature. 1993;363:640–644
  44. Rabbitts TH, Forster A, Larson R, Nathan P. Fusion of the dominant negative transcription regulator CHOP with a novel gene FUS by translocation t(12;16) in malignant liposarcoma. Nat Genet. 1993;4:175–180
  45. Panagopoulos I, Hoglund M, Mertens F, Mandahl N, Mitelman F, Aman P. Fusion of the EWS and CHOP genes in myxoid liposarcoma. Oncogene. 1996;12:489–494
  46. Antonescu CR, Tschernyavsky SJ, Decuseara R, Leung DH, Woodruff JM, Brennan MF, et al. Prognostic impact of P53 status, TLS-CHOP fusion transcript structure, and histological grade in myxoid liposarcoma: a molecular and clinicopathologic study of 82 cases. Clin Cancer Res. 2001;7:3977–3987
  47. Knight JC, Renwick PJ, Dal Cin P, Van den Berghe H, Fletcher CD. Translocation t(12;16)(q13;p11) in myxoid liposarcoma and round cell liposarcoma: molecular and cytogenetic analysis. Cancer Res. 1995;55:24–27
  48. Panagopoulos I, Mandahl N, Ron D, Hoglund M, Nilbert M, Mertens F, et al. Characterization of the CHOP breakpoints and fusion transcripts in myxoid liposarcomas with the 12;16 translocation. Cancer Res. 1994;54:6500–6503
  49. Antonescu CR, Elahi A, Healey JH, Brennan MF, Lui MY, Lewis J, et al. Monoclonality of multifocal myxoid liposarcoma: confirmation by analysis of TLS-CHOP or EWS-CHOP rearrangements. Clin Cancer Res. 2000;6:2788–2793
  50. Oda Y, Yamamoto H, Takahira T, Kobayashi C, Kawaguchi K, Tateishi N, et al. Frequent alteration of p16(INK4a)/p14(ARF) and p53 pathways in the round cell component of myxoid/round cell liposarcoma: p53 gene alterations and reduced p14(ARF) expression both correlate with poor prognosis. J Pathol. 2005;207:410–421
  51. Panagopoulos I, Mertens F, Debiec-Rychter M, Isaksson M, Limon J, Kardas I, et al. Molecular genetic characterization of the EWS/ATF1 fusion gene in clear cell sarcoma of tendons and aponeuroses. Int J Cancer. 2002;99:560–567
  52. Antonescu CR, Tschernyavsky SJ, Woodruff JM, Jungbluth AA, Brennan MF, 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;4:44–52
  53. Zucman J, Delattre O, Desmaze C, Epstein AL, Stenman G, Speleman F, et al. EWS and ATF-1 gene fusion induced by t(12;22) translocation in malignant melanoma of soft parts. Nat Genet. 1993;4:341–345
  54. Coindre JM, Hostein I, Terrier P, Bouvier-Labit C, Collin F, Michels JJ, et al. Diagnosis of clear cell sarcoma by real-time reverse transcriptase-polymerase chain reaction analysis of paraffin embedded tissues: clinicopathologic and molecular analysis of 44 patients from the French sarcoma group. Cancer. 2006;107:1055–1064
  55. Antonescu CR, Nafa K, Segal NH, Dal Cin P, Ladanyi M. EWS-CREB1: a recurrent variant fusion in clear cell sarcoma—association with gastrointestinal location and absence of melanocytic differentiation. Clin Cancer Res. 2006;12:5356–5362
  56. Segal NH, Pavlidis P, Noble WS, Antonescu CR, Viale A, Wesley UV, et al. Classification of clear-cell sarcoma as a subtype of melanoma by genomic profiling. J Clin Oncol. 2003;21:1775–1781
  57. Panagopoulos I, Mertens F, Isaksson M, Mandahl N. Absence of mutations of the BRAF gene in malignant melanoma of soft parts (clear cell sarcoma of tendons and aponeuroses). Cancer Genet Cytogenet. 2005;156:74–76
  58. Langezaal SM, Graadt van Roggen JF, Cleton-Jansen AM, Baelde JJ, Hogendoorn PC. Malignant melanoma is genetically distinct from clear cell sarcoma of tendons and aponeurosis (malignant melanoma of soft parts). Br J Cancer. 2001;84:535–538
  59. Patel RM, Downs-Kelly E, Weiss SW, Folpe AL, Tubbs RR, Tuthill RJ, et al. Dual-color, break-apart fluorescence in situ hybridization for EWS gene rearrangement distinguishes clear cell sarcoma of soft tissue from malignant melanoma. Mod Pathol. 2005;18:1585–1590
  60. Rossi S, Szuhai K, Ijszenga M, Tanke HJ, Zanatta L, Sciot R, et al. EWSR1-CREB1 and EWSR1-ATF1 fusion genes in angiomatoid fibrous histiocytoma. Clin Cancer Res. 2007;13:7322–7328
  61. Antonescu CR, Dal Cin P, Nafa K, Teot LA, Surti U, Fletcher CD, et al. EWSR1-CREB1 is the predominant gene fusion in angiomatoid fibrous histiocytoma. Genes Chromosomes Cancer. 2007;46:1051–1060
  62. Mertens F, Fletcher CD, Antonescu CR, Coindre JM, Colecchia M, Domanski HA, et al. Clinicopathologic and molecular genetic characterization of low-grade fibromyxoid sarcoma, and cloning of a novel FUS/CREB3L1 fusion gene. Lab Invest. 2005;85:408–415
  63. Reid R, de Silva MV, Paterson L, Ryan E, Fisher C. Low-grade fibromyxoid sarcoma and hyalinizing spindle cell tumor with giant rosettes share a common t(7;16)(q34;p11) translocation. Am J Surg Pathol. 2003;27:1229–1236
  64. Storlazzi CT, Mertens F, Nascimento A, Isaksson M, Wejde J, Brosjo O, et al. Fusion of the FUS and BBF2H7 genes in low grade fibromyxoid sarcoma. Hum Mol Genet. 2003;12:2349–2358
  65. Guillou L, Benhattar J, Gengler C, Gallagher G, Ranchere-Vince D, Collin F, et al. Translocation-positive low-grade fibromyxoid sarcoma: clinicopathologic and molecular analysis of a series expanding the morphologic spectrum and suggesting potential relationship to sclerosing epithelioid fibrosarcoma: a study from the French Sarcoma Group. Am J Surg Pathol. 2007;31:1387–1402
  66. Lane KL, Shannon RJ, Weiss SW. Hyalinizing spindle cell tumor with giant rosettes: a distinctive tumor closely resembling low-grade fibromyxoid sarcoma. Am J Surg Pathol. 1997;21:1481–1488
  67. McArthur GA, Demetri GD, van Oosterom A, Heinrich MC, Debiec-Rychter M, Corless CL, et al. Molecular and clinical analysis of locally advanced dermatofibrosarcoma protuberans treated with imatinib: Imatinib Target Exploration Consortium Study B2225. J Clin Oncol. 2005;23:866–873
  68. McArthur G. Molecularly targeted treatment for dermatofibrosarcoma protuberans. Semin Oncol. 2004;31:30–36
  69. Maki RG, Awan RA, Dixon RH, Jhanwar S, Antonescu CR. Differential sensitivity to imatinib of 2 patients with metastatic sarcoma arising from dermatofibrosarcoma protuberans. Int J Cancer. 2002;100:623–626
  70. Rubin BP, Schuetze SM, Eary JF, Norwood TH, Mirza S, Conrad EU, et al. Molecular targeting of platelet-derived growth factor B by imatinib mesylate in a patient with metastatic dermatofibrosarcoma protuberans. J Clin Oncol. 2002;20:3586–3591
  71. Navarro D, Cabrera JJ, Leon L, Chirino R, Fernandez L, Lopez A, et al. Endometrial stromal sarcoma expression of estrogen receptors, progesterone receptors and estrogen-induced srp27 (24K) suggests hormone responsiveness. J Steroid Biochem Mol Biol. 1992;41:589–596
  72. Krumholz BA, Lobovsky FY, Halitsky V. Endolymphatic stromal myosis with pulmonary metastases (Remission with progestin therapy: report of a case). J Reprod Med. 1973;10:85–89
  73. La Quaglia MP, Brennan MF. The clinical approach to desmoplastic small round cell tumor. Surg Oncol. 2000;9:77–81
  74. Ladanyi M, Lui MY, Antonescu CR, Krause-Boehm A, Meindl A, Argani P, et al. The der(17)t(X;17)(p11;q25) of human alveolar soft part sarcoma fuses the TFE3 transcription factor gene to ASPL, a novel gene at 17q25. Oncogene. 2001;20:48–57
  75. Grosso F, Jones RL, Demetri GD, Judson IR, Blay JY, Le Cesne A, et al. Efficacy of trabectedin (ecteinascidin-743) in advanced pretreated myxoid liposarcomas: a retrospective study. Lancet Oncol. 2007;8:595–602
  76. Tavecchio M, Simone M, Erba E, Chiolo I, Liberi G, Foiani M, et al. Role of homologous recombination in trabectedin-induced DNA damage. Eur J Cancer. 2008;44:609–618
  77. D'Incalci M, Brunelli D, Marangon E, Simone M, Tavecchio M, Gescher A, et al. Modulation of gene transcription by natural products—a viable anticancer strategy. Curr Pharm Des. 2007;13:2744–2750
  78. D'Incalci M, Erba E, Damia G, Galliera E, Carrassa L, Marchini S, et al. Unique features of the mode of action of ET-743. Oncologist. 2002;7:210–216
  79. Damia G, Silvestri S, Carrassa L, Filiberti L, Faircloth GT, Liberi G, et al. Unique pattern of ET-743 activity in different cellular systems with defined deficiencies in DNA-repair pathways. Int J Cancer. 2001;92:583–588
  80. Bonfanti M, La Valle E, Fernandez Sousa Faro JM, Faircloth G, Caretti G, Mantovani R, et al. Effect of ecteinascidin-743 on the interaction between DNA binding proteins and DNA. Anticancer Drug Des. 1999;14:179–186
  81. Minuzzo M, Marchini S, Broggini M, Faircloth G, D'Incalci M, Mantovani R. Interference of transcriptional activation by the antineoplastic drug ecteinascidin-743. Proc Natl Acad Sci U S A. 2000;97:6780–6784
  82. Le Cesne A, Blay JY, Judson I, Van Oosterom A, Verweij J, Radford J, et al. Phase II study of ET-743 in advanced soft tissue sarcomas: a European Organisation for the Research and Treatment of Cancer (EORTC) Soft Tissue and Bone Sarcoma Group trial. J Clin Oncol. 2005;23:576–584
  83. Garcia-Carbonero R, Supko JG, Manola J, Seiden MV, Harmon D, Ryan DP, et al. Phase II and pharmacokinetic study of ecteinascidin 743 in patients with progressive sarcomas of soft tissues refractory to chemotherapy. J Clin Oncol. 2004;22:1480–1490
  84. Morgan JA, Le Cesne A, Chawla S, von Mehren M, Schuetze S, Casali PG, et al. Randomized phase II study of trabectedin in patients with liposarcoma and leiomyosarcoma after failure of prior anthracylines and ifosfamide [abstract]. J Clin Oncol. 2007;25:10060

Disclosures Paolo G. Casali: Pharma Mar, Johnson & Johnson (research funds), Pharma Mar (honoraria); Maurizio D'Incalci: Pharma Mar (research funds).Other authors: none

PII: S0093-7754(09)00104-3

doi: 10.1053/j.seminoncol.2009.06.004

Seminars in Oncology
Volume 36, Issue 4 , Pages 312-323 , August 2009