Gene Translocations in Musculoskeletal Neoplasms

Symposium: Molecular Genetics in Sarcoma

Abstract

Establishing the best diagnosis for musculoskeletal neoplasms requires a multidisciplinary approach using clinical, radiographic, and histologic analyses. Despite this rigorous approach, establishing accurate diagnoses and prognoses remains challenging. Improved diagnostic methods are expected as unique molecular signals for specific bone and soft tissue cancers are identified. We performed a systematic review of the best available evidence to explore three major applications of molecular genetics that will best benefit clinical management of musculoskeletal neoplasms: diagnostic, prognostic, and therapeutic applications. The specific questions addressed in this systematic review are: (1) What sets of histopathologic sarcoma subtypes will benefit from molecular evaluation and diagnosis? (2) What molecular methods are best applied to histopathologic sarcomas to distinguish between major subtypes? (3) How do the molecular patterns discovered on genetic diagnosis affect prognosis of certain sarcomas? (4) Which sarcoma translocations can benefit from an improved response and outcome using existing and forthcoming pharmacogenetic approaches targeting molecular events? This review summarizes recent advances in molecular genetics that are available and will soon be available to clinicians to better predict outcomes and subsequently help make future treatment decisions.

Level of Evidence: Level IV, diagnostic study. See the Guidelines for Authors for a complete description of levels of evidence.

References

  1. 1.
    Allander SV, Illei PB, Chen Y, Antonescu CR, Bittner M, Ladanyi M, Meltzer PS. Expression profiling of synovial sarcoma by cDNA microarrays: association of ERBB2, IGFBP2, and ELF3 with epithelial differentiation. Am J Pathol. 2002;161:1587–1595.PubMedGoogle Scholar
  2. 2.
    Ambrosini G, Sambol EB, Carvajal D, Vassilev LT, Singer S, Schwartz GK. Mouse double minute antagonist nutlin-3a enhances chemotherapy-induced apoptosis in cancer cells with mutant p53 by activating E2F1. Oncogene. 2007;26:3473–3481.PubMedGoogle Scholar
  3. 3.
    Anderson J, Gordon T, McManus A, Mapp T, Gould S, Kelsey A, McDowell H, Pinkerton R, Shipley J, Pritchard-Jones K, UK Children’s Cancer Study Group (UKCCSG) and the UK Cancer Cytogenetics Group. Detection of the PAX3-FKHR fusion gene in paediatric rhabdomyosarcoma: a reproducible predictor of outcome? Br J Cancer. 2001;85:831–835.PubMedGoogle Scholar
  4. 4.
    Anderson J, Ramsay A, Gould S, Pritchard-Jones K. PAX3-FKHR induces morphological change and enhances cellular proliferation and invasion in rhabdomyosarcoma. Am J Pathol. 2001;159:1089–1096.PubMedGoogle Scholar
  5. 5.
    Antonescu CR. The role of genetic testing in soft tissue sarcoma. Histopathology. 2006;48:13–21.PubMedGoogle Scholar
  6. 6.
    Antonescu CR, Elahi A, Humphrey M, Lui MY, Healey JH, Brennan MF, Woodruff JM, Jhanwar SC, Ladanyi M. Specificity of TLS-CHOP rearrangement for classic myxoid/round cell liposarcoma: absence in predominantly myxoid well-differentiated liposarcomas. J Mol Diagn. 2000;2:132–138.PubMedGoogle Scholar
  7. 7.
    Argani P, Fritsch M, Kadkol SS, Schuster A, Beckwith JB, Perlman EJ. Detection of the ETV6-NTRK3 chimeric RNA of infantile fibrosarcoma/cellular congenital mesoblastic nephroma in paraffin-embedded tissue: application to challenging pediatric renal stromal tumors. Mod Pathol. 2000;13:29–36.PubMedGoogle Scholar
  8. 8.
    Athale UH, Shurtleff SA, Jenkins JJ, Poquette CA, Tan M, Downing JR, Pappo AS. Use of reverse transcriptase polymerase chain reaction for diagnosis and staging of alveolar rhabdomyosarcoma, Ewing sarcoma family of tumors, and desmoplastic small round cell tumor. J Pediatr Hematol Oncol. 2001;23:99–104.PubMedGoogle Scholar
  9. 9.
    Atiye J, Wolf M, Kaur S, Monni O, Bohling T, Kivioja A, Tas E, Serra M, Tarkkanen M, Knuutila S. Gene amplifications in osteosarcoma-CGH microarray analysis. Genes Chromosomes Cancer. 2005;42:158–163.PubMedGoogle Scholar
  10. 10.
    Baird K, Davis S, Antonescu CR, Harper UL, Walker RL, Chen Y, Glatfelter AA, Duray PH, Meltzer PS. Gene expression profiling of human sarcomas: insights into sarcoma biology. Cancer Res. 2005;65:9226–9235.PubMedGoogle Scholar
  11. 11.
    Ballaux F, Debiec-Rychter M, De Wever I, Sciot R. Chondroid lipoma is characterized by t(11;16)(q13;p12–13). Virchows Arch. 2004;444:208–210.PubMedGoogle Scholar
  12. 12.
    Barr FG, Womer RB. Molecular diagnosis of Ewing family tumors: too many fusions…? J Mol Diagn. 2007;9:437–440.PubMedGoogle Scholar
  13. 13.
    Bayani J, Squire JA. Advances in the detection of chromosomal aberrations using spectral karyotyping. Clin Genet. 2001;59:65–73.PubMedGoogle Scholar
  14. 14.
    Bode-Lesniewska B, Frigerio S, Exner U, Abdou MT, Moch H, Zimmermann DR. Relevance of translocation type in myxoid liposarcoma and identification of a novel EWSR1-DDIT3 fusion. Genes Chromosomes Cancer. 2007;46:961–971.PubMedGoogle Scholar
  15. 15.
    Bovee JV, van den Broek LJ, Cleton-Jansen AM, Hogendoorn PC. Up-regulation of PTHrP and bcl-2 expression characterizes the progression of osteochondroma towards peripheral chondrosarcoma and is a late event in central chondrosarcoma. Lab Invest. 2000;80:1925–1934.PubMedGoogle Scholar
  16. 16.
    Bridge JA, Nelson M, Orndal C, Bhatia P, Neff JR. Clonal karyotypic abnormalities of the hereditary multiple exostoses chromosomal loci 8q24.1 (EXT1) and 11p11–12 (EXT2) in patients with sporadic and hereditary osteochondromas. Cancer. 1998;82:1657–1663.PubMedGoogle Scholar
  17. 17.
    Butler MG, Dahir GA, Hedges LK, Juliao SF, Sciadini MF, Schwartz HS. Cytogenetic, telomere, and telomerase studies in five surgically managed lumbosacral chordomas. Cancer Genet Cytogenet. 1995;85:51–57.PubMedGoogle Scholar
  18. 18.
    Chang CC, Shidham VB. Molecular genetics of pediatric soft tissue tumors: clinical application. J Mol Diagn. 2003;5:143–154.PubMedGoogle Scholar
  19. 19.
    Dal Cin P, Kools P, Sciot R, De Wever I, Van Damme B, Van de Ven W, Van den Berghe H. Cytogenetic and fluorescence in situ hybridization investigation of ring chromosomes characterizing a specific pathologic subgroup of adipose tissue tumors. Cancer Genet Cytogenet. 1993;68:85–90.PubMedGoogle Scholar
  20. 20.
    Dal Cin P, Sciot R, Polito P, Stas M, de Wever I, Cornelis A, Van den Berghe H. Lesions of 13q may occur independently of deletion of 16q in spindle cell/pleomorphic lipomas. Histopathology. 1997;31:222–225.PubMedGoogle Scholar
  21. 21.
    Dal Cin P, Sciot R, Speleman F, Samson I, Laureys G, de Potter C, Meire F, van Damme B, van den Berghe H. Chromosome aberrations in fibrous dysplasia. Cancer Genet Cytogenet. 1994;77:114–117.PubMedGoogle Scholar
  22. 22.
    Davicioni E, Finckenstein FG, Shahbazian V, Buckley JD, Triche TJ, Anderson MJ. Identification of a PAX-FKHR gene expression signature that defines molecular classes and determines the prognosis of alveolar rhabdomyosarcomas. Cancer Res. 2006;66:6936–6946.PubMedGoogle Scholar
  23. 23.
    de Alava E, Kawai A, Healey JH, Fligman I, Meyers PA, Huvos AG, Gerald WL, Jhanwar SC, Argani P, Antonescu CR, Pardo-Mindan FJ, Ginsberg J, Womer R, Lawlor ER, Wunder J, Andrulis I, Sorensen PH, Barr FG, Ladanyi M. EWS-FLI1 fusion transcript structure is an independent determinant of prognosis in Ewing’s sarcoma. J Clin Oncol. 1998;16:1248–1255.PubMedGoogle Scholar
  24. 24.
    de Alava E, Panizo A, Antonescu CR, Huvos AG, Pardo-Mindan FJ, Barr FG, Ladanyi M. Association of EWS-FLI1 type 1 fusion with lower proliferative rate in Ewing’s sarcoma. Am J Pathol. 2000;156:849–855.PubMedGoogle Scholar
  25. 25.
    Dhaini HR, Thomas DG, Giordano TJ, Johnson TD, Biermann JS, Leu K, Hollenberg PF, Baker LH. Cytochrome P450 CYP3A4/5 expression as a biomarker of outcome in osteosarcoma. J Clin Oncol. 2003;21:2481–2485.PubMedGoogle Scholar
  26. 26.
    Evans CH, Ghivizzani SC, Herndon JH, Robbins PD. Gene therapy for the treatment of musculoskeletal diseases. J Am Acad Orthop Surg. 2005;13:230–242.PubMedGoogle Scholar
  27. 27.
    Evans CH, Ghivizzani SC, Robbins PD. The 2003 Nicolas Andry Award. Orthopaedic gene therapy. Clin Orthop Relat Res. 2000;429:316–329.Google Scholar
  28. 28.
    Fletcher CD, Akerman M, Dal Cin P, de Wever I, Mandahl N, Mertens F, Mitelman F, Rosai J, Rydholm A, Sciot R, Tallini G, van den Berghe H, van de Ven W, Vanni R, Willen H. Correlation between clinicopathological features and karyotype in lipomatous tumors. A report of 178 cases from the chromosomes and morphology (CHAMP) collaborative study group. Am J Pathol. 1996;148:623–630.PubMedGoogle Scholar
  29. 29.
    Galili N, Davis RJ, Fredericks WJ, Mukhopadhyay S, Rauscher FJ 3rd, Emanuel BS, Rovera G, Barr FG. Fusion of a fork head domain gene to PAX3 in the solid tumour alveolar rhabdomyosarcoma. Nat Genet. 1993;5:230–235.PubMedGoogle Scholar
  30. 30.
    Gasparini G, Longo R, Fanelli M, Teicher BA. Combination of antiangiogenic therapy with other anticancer therapies: results, challenges, and open questions. J Clin Oncol. 2005;23:1295–1311.PubMedGoogle Scholar
  31. 31.
    Gisselsson D, Hibbard MK, Dal Cin P, Sciot R, Hsi BL, Kozakewich HP, Fletcher JA. PLAG1 alterations in lipoblastoma: involvement in varied mesenchymal cell types and evidence for alternative oncogenic mechanisms. Am J Pathol. 2001;159:955–962.PubMedGoogle Scholar
  32. 32.
    Gisselsson D, Hoglund M, Mertens F, Dal Cin P, Mandahl N. Hibernomas are characterized by homozygous deletions in the multiple endocrine neoplasia type I region. Metaphase fluorescence in situ hybridization reveals complex rearrangements not detected by conventional cytogenetics. Am J Pathol. 1999;155:61–66.PubMedGoogle Scholar
  33. 33.
    Graadt van Roggen JF, Bovee JV, Morreau J, Hogendoorn PC. Diagnostic and prognostic implications of the unfolding molecular biology of bone and soft tissue tumours. J Clin Pathol. 1999;52:481–489.CrossRefGoogle Scholar
  34. 34.
    Grazioli L, Olivetti L, Fugazzola C, Benetti A, Stanga C, Dettori E, Gallo C, Matricardi L, Giacobbe A, Chiesa A. The pseudocapsule in hepatocellular carcinoma: correlation between dynamic MR imaging and pathology. Eur Radiol. 1999;9:62–67.PubMedGoogle Scholar
  35. 35.
    Grosso F, Jones RL, Demetri GD, Judson IR, Blay JY, Le Cesne A, Sanfilippo R, Casieri P, Collini P, Dileo P, Spreafico C, Stacchiotti S, Tamborini E, Tercero JC, Jimeno J, D’Incalci M, Gronchi A, Fletcher JA, Pilotti S, Casali PG. Efficacy of trabectedin (ecteinascidin-743) in advanced pretreated myxoid liposarcomas: a retrospective study. Lancet Oncol. 2007;8:595–602.PubMedGoogle Scholar
  36. 36.
    Guillou L, Benhattar J, Bonichon F, Gallagher G, Terrier P, Stauffer E, Somerhausen Nde S, Michels JJ, Jundt G, Vince DR, Taylor S, Genevay M, Collin F, Trassard M, Coindre JM. Histologic grade, but not SYT-SSX fusion type, is an important prognostic factor in patients with synovial sarcoma: a multicenter, retrospective analysis. J Clin Oncol. 2004;22:4040–4050.PubMedGoogle Scholar
  37. 37.
    Guo Y, Zi X, Koontz Z, Kim A, Xie J, Gorlick R, Holcombe RF, Hoang BH. Blocking Wnt/LRP5 signaling by a soluble receptor modulates the epithelial to mesenchymal transition and suppresses met and metalloproteinases in osteosarcoma saos-2 cells. J Orthop Res. 2007;25:964–971.PubMedGoogle Scholar
  38. 38.
    Hattori Y, Maitani Y. Folate-linked lipid-based nanoparticle for targeted gene delivery. Curr Drug Deliv. 2005;2:243–252.PubMedGoogle Scholar
  39. 39.
    Hauben E, van den Broek LC, Van Marck E, Hogendoorn PC. Adamantinoma-like Ewing’s sarcoma and Ewing’s-like adamantinoma. The t(11; 22), t(21; 22) status. J Pathol. 2001;195:218–221.PubMedGoogle Scholar
  40. 40.
    Hazelbag HM, Wessels JW, Mollevangers P, van den Berg E, Molenaar WM, Hogendoorn PC. Cytogenetic analysis of adamantinoma of long bones: further indications for a common histogenesis with osteofibrous dysplasia. Cancer Genet Cytogenet. 1997;97:5–11.PubMedGoogle Scholar
  41. 41.
    Hill DA, O’Sullivan MJ, Zhu X, Vollmer RT, Humphrey PA, Dehner LP, Pfeifer JD. Practical application of molecular genetic testing as an aid to the surgical pathologic diagnosis of sarcomas: a prospective study. Am J Surg Pathol. 2002;26:965–977.PubMedGoogle Scholar
  42. 42.
    Hopyan S, Gokgoz N, Poon R, Gensure RC, Yu C, Cole WG, Bell RS, Juppner H, Andrulis IL, Wunder JS, Alman BA. A mutant PTH/PTHrP type I receptor in enchondromatosis. Nat Genet. 2002;30:306–310.PubMedGoogle Scholar
  43. 43.
    Horie N, Murata H, Nishigaki Y, Matsui T, Segawa H, Nogawa M, Yuasa T, Kimura S, Maekawa T, Fushiki S, Kubo T. The third-generation bisphosphonates inhibit proliferation of murine osteosarcoma cells with induction of apoptosis. Cancer Lett. 2006;238:111–118.PubMedGoogle Scholar
  44. 44.
    Hu-Lieskovan S, Heidel JD, Bartlett DW, Davis ME, Triche TJ. Sequence-specific knockdown of EWS-FLI1 by targeted, nonviral delivery of small interfering RNA inhibits tumor growth in a murine model of metastatic Ewing’s sarcoma. Cancer Res. 2005;65:8984–8992.PubMedGoogle Scholar
  45. 45.
    Inagaki H, Nagasaka T, Otsuka T, Sugiura E, Nakashima N, Eimoto T. Association of SYT-SSX fusion types with proliferative activity and prognosis in synovial sarcoma. Mod Pathol. 2000;13:482–488.PubMedGoogle Scholar
  46. 46.
    Ito T, Ouchida M, Morimoto Y, Yoshida A, Jitsumori Y, Ozaki T, Sonobe H, Inoue H, Shimizu K. Significant growth suppression of synovial sarcomas by the histone deacetylase inhibitor FK228 in vitro and in vivo. Cancer Lett. 2005;224:311–319.PubMedGoogle Scholar
  47. 47.
    Ivkovic A, Pascher A, Hudetz D, Jelic M, Haspl M, Windhager R, Pecina M. Current concepts in gene therapy of the musculoskeletal system. Acta Chir Orthop Traumatol Cech. 2006;73:115–122.PubMedGoogle Scholar
  48. 48.
    Jones DH, Nakashima T, Sanchez OH, Kozieradzki I, Komarova SV, Sarosi I, Morony S, Rubin E, Sarao R, Hojilla CV, Komnenovic V, Kong YY, Schreiber M, Dixon SJ, Sims SM, Khokha R, Wada T, Penninger JM. Regulation of cancer cell migration and bone metastasis by RANKL. Nature. 2006;440:692–696.PubMedGoogle Scholar
  49. 49.
    Kawai A, Woodruff J, Healey JH, Brennan MF, Antonescu CR, Ladanyi M. SYT-SSX gene fusion as a determinant of morphology and prognosis in synovial sarcoma. N Engl J Med. 1998;338:153–160.PubMedGoogle Scholar
  50. 50.
    Kelly KM, Womer RB, Barr FG. PAX3-FKHR and PAX7-FKHR gene fusions in rhabdomyosarcoma. J Pediatr Hematol Oncol. 1998;20:517–518.PubMedGoogle Scholar
  51. 51.
    Kerob D, Pedeutour F, Leboeuf C, Verola O, de Kerviler E, Servant JM, Sarandi F, Bousquet G, Madelaine-Chambrin I, Pruvost C, Calvo F, Janin A, Lebbe C. Value of cytogenetic analysis in the treatment of dermatofibrosarcoma protuberans. J Clin Oncol. 2008;26:1757–1759.PubMedGoogle Scholar
  52. 52.
    Kilpatrick SE, Doyon J, Choong PF, Sim FH, Nascimento AG. The clinicopathologic spectrum of myxoid and round cell liposarcoma. A study of 95 cases. Cancer. 1996;77:1450–1458.PubMedGoogle Scholar
  53. 53.
    Kiselyov AS. Targeting the hedgehog signaling pathway with small molecules. Anticancer Agents Med Chem. 2006;6:445–449.PubMedGoogle Scholar
  54. 54.
    Knezevich SR, McFadden DE, Tao W, Lim JF, Sorensen PH. A novel ETV6-NTRK3 gene fusion in congenital fibrosarcoma. Nat Genet. 1998;18:184–187.PubMedGoogle Scholar
  55. 55.
    Kong Y, Poon R, Nadesan P, Di Muccio T, Fodde R, Khokha R, Alman BA. Matrix metalloproteinase activity modulates tumor size, cell motility, and cell invasiveness in murine aggressive fibromatosis. Cancer Res. 2004;64:5795–5803.PubMedGoogle Scholar
  56. 56.
    Ladanyi M, Antonescu CR, Leung DH, Woodruff JM, Kawai A, Healey JH, Brennan MF, Bridge JA, Neff JR, Barr FG, Goldsmith JD, Brooks JS, Goldblum JR, Ali SZ, Shipley J, Cooper CS, Fisher C, Skytting B, Larsson O. Impact of SYT-SSX fusion type on the clinical behavior of synovial sarcoma: a multi-institutional retrospective study of 243 patients. Cancer Res. 2002;62:135–140.PubMedGoogle Scholar
  57. 57.
    Ladanyi M, Gerald W. Fusion of the EWS and WT1 genes in the desmoplastic small round cell tumor. Cancer Res. 1994;54:2837–2840.PubMedGoogle Scholar
  58. 58.
    Ladanyi M, Lui MY, Antonescu CR, Krause-Boehm A, Meindl A, Argani P, Healey JH, Ueda T, Yoshikawa H, Meloni-Ehrig A, Sorensen PH, Mertens F, Mandahl N, van den Berghe H, Sciot R, Cin PD, Bridge J. 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.PubMedGoogle Scholar
  59. 59.
    Lazar AJ, Trent JC, Lev D. Sarcoma molecular testing: diagnosis and prognosis. Curr Oncol Rep. 2007;9:309–315.PubMedGoogle Scholar
  60. 60.
    Lugo-Vicente H. Molecular biology and genetics affecting pediatric solid tumors. Bol Asoc Med P R. 2000;92:72–82.PubMedGoogle Scholar
  61. 61.
    Ma Z, Hill DA, Collins MH, Morris SW, Sumegi J, Zhou M, Zuppan C, Bridge JA. Fusion of ALK to the ran-binding protein 2 (RANBP2) gene in inflammatory myofibroblastic tumor. Genes Chromosomes Cancer. 2003;37:98–105.PubMedGoogle Scholar
  62. 62.
    Maki RG. Soft tissue sarcoma as a model disease to examine cancer immunotherapy. Curr Opin Oncol. 2001;13:270–274.PubMedGoogle Scholar
  63. 63.
    Mandahl N, Hoglund M, Mertens F, Rydholm A, Willen H, Brosjo O, Mitelman F. Cytogenetic aberrations in 188 benign and borderline adipose tissue tumors. Genes Chromosomes Cancer. 1994;9:207–215.PubMedGoogle Scholar
  64. 64.
    Mertens F, Fletcher CD, Antonescu CR, Coindre JM, Colecchia M, Domanski HA, Downs-Kelly E, Fisher C, Goldblum JR, Guillou L, Reid R, Rosai J, Sciot R, Mandahl N, Panagopoulos I. 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.PubMedGoogle Scholar
  65. 65.
    Mezzelani A, Mariani L, Tamborini E, Agus V, Riva C, Lo Vullo S, Fabbri A, Stumbo M, Azzarelli A, Casali PG, Gronchi A, Sozzi G, Pierotti MA, Pilotti S. SYT-SSX fusion genes and prognosis in synovial sarcoma. Br J Cancer. 2001;85:1535–1539.PubMedGoogle Scholar
  66. 66.
    Micci F, Teixeira MR, Bjerkehagen B, Heim S. Characterization of supernumerary rings and giant marker chromosomes in well-differentiated lipomatous tumors by a combination of G-banding, CGH, M-FISH, and chromosome- and locus-specific FISH. Cytogenet Genome Res. 2002;97:13–19.PubMedGoogle Scholar
  67. 67.
    Miettinen M. From morphological to molecular diagnosis of soft tissue tumors. Adv Exp Med Biol. 2006;587:99–113.PubMedGoogle Scholar
  68. 68.
    Mitelman Database of Chromosome Aberrations in Cancer (2007). Mitelman F, Johansson B, Mertens F, eds. Available at: http://cgap.nci.nih.gov/Chromosomes/Mitelman. Accessed August 15, 2007.
  69. 69.
    Morcuende JA, Buckwalter JA. New advances in the molecular biology of musculoskeletal neoplasms. Iowa Orthop J. 1997;17:115–120.PubMedGoogle Scholar
  70. 70.
    Muro-Cacho CA. The role of immunohistochemistry in the diagnosis of primary tumors of the bone. Cancer Control. 1998;5:561–569.PubMedGoogle Scholar
  71. 71.
    Nagayama S, Fukukawa C, Katagiri T, Okamoto T, Aoyama T, Oyaizu N, Imamura M, Toguchida J, Nakamura Y. Therapeutic potential of antibodies against FZD 10, a cell-surface protein, for synovial sarcomas. Oncogene. 2005;24:6201–6212.PubMedGoogle Scholar
  72. 72.
    Naumann S, Krallman PA, Unni KK, Fidler ME, Neff JR, Bridge JA. Translocation der(13;21)(q10;q10) in skeletal and extraskeletal mesenchymal chondrosarcoma. Mod Pathol. 2002;15:572–576.PubMedGoogle Scholar
  73. 73.
    Nilsson G, Skytting B, Xie Y, Brodin B, Perfekt R, Mandahl N, Lundeberg J, Uhlen M, Larsson O. The SYT-SSX1 variant of synovial sarcoma is associated with a high rate of tumor cell proliferation and poor clinical outcome. Cancer Res. 1999;59:3180–3184.PubMedGoogle Scholar
  74. 74.
    Nilsson M, Hoglund M, Panagopoulos I, Sciot R, Dal Cin P, Debiec-Rychter M, Mertens F, Mandahl N. Molecular cytogenetic mapping of recurrent chromosomal breakpoints in tenosynovial giant cell tumors. Virchows Arch. 2002;441:475–480.PubMedGoogle Scholar
  75. 75.
    Oliveira AM, Fletcher CD. Molecular prognostication for soft tissue sarcomas: are we ready yet? J Clin Oncol. 2004;22:4031–4034.PubMedGoogle Scholar
  76. 76.
    Panagopoulos I, Mertens F, Isaksson M, Limon J, Gustafson P, Skytting B, Akerman M, Sciot R, Dal Cin P, Samson I, Iliszko M, Ryoe J, Debiec-Rychter M, Szadowska A, Brosjo O, Larsson O, Rydholm A, Mandahl N. Clinical impact of molecular and cytogenetic findings in synovial sarcoma. Genes Chromosomes Cancer. 2001;31:362–372.PubMedGoogle Scholar
  77. 77.
    Panagopoulos I, Storlazzi CT, Fletcher CD, Fletcher JA, Nascimento A, Domanski HA, Wejde J, Brosjo O, Rydholm A, Isaksson M, Mandahl N, Mertens F. The chimeric FUS/CREB3l2 gene is specific for low-grade fibromyxoid sarcoma. Genes Chromosomes Cancer. 2004;40:218–228.PubMedGoogle Scholar
  78. 78.
    Partinen M, Hirvonen K, Hublin C, Halavaara M, Hiltunen H. Effects of after-midnight intake of zolpidem and temazepam on driving ability in women with non-organic insomnia. Sleep Med. 2003;4:553–561.PubMedGoogle Scholar
  79. 79.
    Peter M, Couturier J, Pacquement H, Michon J, Thomas G, Magdelenat H, Delattre O. A new member of the ETS family fused to EWS in Ewing tumors. Oncogene. 1997;14:1159–1164.PubMedGoogle Scholar
  80. 80.
    Qi H, Dal Cin P, Hernandez JM, Garcia JL, Sciot R, Fletcher C, Van Eyken P, De Wever I, Van den Berghe H. Trisomies 8 and 20 in desmoid tumors. Cancer Genet Cytogenet. 1996;92:147–149.PubMedGoogle Scholar
  81. 81.
    Qualman SJ, Morotti RA. Risk assignment in pediatric soft-tissue sarcomas: an evolving molecular classification. Curr Oncol Rep. 2002;4:123–130.PubMedGoogle Scholar
  82. 82.
    Rabbitts TH. Chromosomal translocations in human cancer. Nature. 1994;372:143–149.PubMedGoogle Scholar
  83. 83.
    Ragland BD, Bell WC, Lopez RR, Siegal GP. Cytogenetics and molecular biology of osteosarcoma. Lab Invest. 2002;82:365–373.PubMedGoogle Scholar
  84. 84.
    Rydholm A. Chromosomal aberrations in musculoskeletal tumours: clinical importance. J Bone Joint Surg Br. 1996;78:501–506.PubMedGoogle Scholar
  85. 85.
    Sakimura R, Tanaka K, Nakatani F, Matsunobu T, Li X, Hanada M, Okada T, Nakamura T, Matsumoto Y, Iwamoto Y. Antitumor effects of histone deacetylase inhibitor on Ewing’s family tumors. Int J Cancer. 2005;116:784–792.PubMedGoogle Scholar
  86. 86.
    Sakimura R, Tanaka K, Yamamoto S, Matsunobu T, Li X, Hanada M, Okada T, Nakamura T, Li Y, Iwamoto Y. The effects of histone deacetylase inhibitors on the induction of differentiation in chondrosarcoma cells. Clin Cancer Res. 2007;13:275–282.PubMedGoogle Scholar
  87. 87.
    Sandberg AA, Bridge JA. Updates on the cytogenetics and molecular genetics of bone and soft tissue tumors: clear cell sarcoma (malignant melanoma of soft parts). Cancer Genet Cytogenet. 2001;130:1–7.PubMedGoogle Scholar
  88. 88.
    Sandberg AA, Bridge JA. Updates on the cytogenetics and molecular genetics of bone and soft tissue tumors: chondrosarcoma and other cartilaginous neoplasms. Cancer Genet Cytogenet. 2003;143:1–31.PubMedGoogle Scholar
  89. 89.
    Scappaticci FA, Marina N. New molecular targets and biological therapies in sarcomas. Cancer Treat Rev. 2001;27:317–326.PubMedGoogle Scholar
  90. 90.
    Schwartz GK, Shah MA. Targeting the cell cycle: a new approach to cancer therapy. J Clin Oncol. 2005;23:9408–9421.PubMedGoogle Scholar
  91. 91.
    Sciot R, Dorfman H, Brys P, Dal Cin P, De Wever I, Fletcher CD, Jonson K, Mandahl N, Mertens F, Mitelman F, Rosai J, Rydholm A, Samson I, Tallini G, Van den Berghe H, Vanni R, Willen H. Cytogenetic-morphologic correlations in aneurysmal bone cyst, giant cell tumor of bone and combined lesions. A report from the CHAMP study group. Mod Pathol. 2000;13:1206–1210.PubMedGoogle Scholar
  92. 92.
    Simon MP, Pedeutour F, Sirvent N, Grosgeorge J, Minoletti F, Coindre JM, Terrier-Lacombe MJ, Mandahl N, Craver RD, Blin N, Sozzi G, Turc-Carel C, O’Brien KP, Kedra D, Fransson I, Guilbaud C, Dumanski JP. Deregulation of the platelet-derived growth factor B-chain gene via fusion with collagen gene COL1A1 in dermatofibrosarcoma protuberans and giant-cell fibroblastoma. Nat Genet. 1997;15:95–98.PubMedGoogle Scholar
  93. 93.
    Singer S, Socci ND, Ambrosini G, Sambol E, Decarolis P, Wu Y, O’Connor R, Maki R, Viale A, Sander C, Schwartz GK, Antonescu CR. Gene expression profiling of liposarcoma identifies distinct biological types/subtypes and potential therapeutic targets in well-differentiated and dedifferentiated liposarcoma. Cancer Res. 2007;67:6626–6636.PubMedGoogle Scholar
  94. 94.
    Sjogren H, Meis-Kindblom J, Kindblom LG, Aman P, Stenman G. Fusion of the EWS-related gene TAF2N to TEC in extraskeletal myxoid chondrosarcoma. Cancer Res. 1999;59:5064–5067.PubMedGoogle Scholar
  95. 95.
    Sjogren H, Meis-Kindblom JM, Orndal C, Bergh P, Ptaszynski K, Aman P, Kindblom LG, Stenman G. Studies on the molecular pathogenesis of extraskeletal myxoid chondrosarcoma-cytogenetic, molecular genetic, and cDNA microarray analyses. Am J Pathol. 2003;162:781–792.PubMedGoogle Scholar
  96. 96.
    Skytting B, Nilsson G, Brodin B, Xie Y, Lundeberg J, Uhlen M, Larsson O. A novel fusion gene, SYT-SSX4, in synovial sarcoma. J Natl Cancer Inst. 1999;91:974–975.PubMedGoogle Scholar
  97. 97.
    Sonnemann J, Dreyer L, Hartwig M, Palani CD, Hong le TT, Klier U, Broker B, Volker U, Beck JF. Histone deacetylase inhibitors induce cell death and enhance the apoptosis-inducing activity of TRAIL in Ewing’s sarcoma cells. J Cancer Res Clin Oncol. 2007;133:847–858.PubMedGoogle Scholar
  98. 98.
    Sorensen PH, Lynch JC, Qualman SJ, Tirabosco R, Lim JF, Maurer HM, Bridge JA, Crist WM, Triche TJ, Barr FG. 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.PubMedGoogle Scholar
  99. 99.
    Sugarbaker PH, Malawer MM. Musculoskeletal Surgery for Cancer: Principles, Techniques. New York, NY: Thieme Medical Publishers; 1992, p. 4.Google Scholar
  100. 100.
    Sukov WR, Cheville JC, Carlson AW, Shearer BM, Piatigorsky EJ, Grogg KL, Sebo TJ, Sinnwell JP, Ketterling RP. Utility of ALK-1 protein expression and ALK rearrangements in distinguishing inflammatory myofibroblastic tumor from malignant spindle cell lesions of the urinary bladder. Mod Pathol. 2007;20:592–603.PubMedGoogle Scholar
  101. 101.
    Tallini G, Akerman M, Dal Cin P, De Wever I, Fletcher CD, Mandahl N, Mertens F, Mitelman F, Rosai J, Rydholm A, Sciot R, Van den Berghe H, Van den Ven W, Vanni R, Willen H. Combined morphologic and karyotypic study of 28 myxoid liposarcomas. Implications for a revised morphologic typing, (a report from the CHAMP group). Am J Surg Pathol. 1996;20:1047–1055.PubMedGoogle Scholar
  102. 102.
    Tiet TD, Hopyan S, Nadesan P, Gokgoz N, Poon R, Lin AC, Yan T, Andrulis IL, Alman BA, Wunder JS. Constitutive hedgehog signaling in chondrosarcoma up-regulates tumor cell proliferation. Am J Pathol. 2006;168:321–330.PubMedGoogle Scholar
  103. 103.
    Triche TJ, Schofield D, Buckley J. DNA microarrays in pediatric cancer. Cancer J. 2001;7:2–15.PubMedGoogle Scholar
  104. 104.
    Waters BL, Panagopoulos I, Allen EF. Genetic characterization of angiomatoid fibrous histiocytoma identifies fusion of the FUS and ATF-1 genes induced by a chromosomal translocation involving bands 12q13 and 16p11. Cancer Genet Cytogenet. 2000;121:109–116.PubMedGoogle Scholar
  105. 105.
    Willeke F, Ridder R, Mechtersheimer G, Schwarzbach M, Duwe A, Weitz J, Lehnert T, Herfarth C, von Knebel Doeberitz M. Analysis of FUS-CHOP fusion transcripts in different types of soft tissue liposarcoma and their diagnostic implications. Clin Cancer Res. 1998;4:1779–1784.PubMedGoogle Scholar
  106. 106.
    Worley BS, van den Broeke LT, Goletz TJ, Pendleton CD, Daschbach EM, Thomas EK, Marincola FM, Helman LJ, Berzofsky JA. Antigenicity of fusion proteins from sarcoma-associated chromosomal translocations. Cancer Res. 2001;61:6868–6875.PubMedGoogle Scholar
  107. 107.
    Wu C, Wei Q, Utomo V, Nadesan P, Whetstone H, Kandel R, Wunder JS, Alman BA. Side population cells isolated from mesenchymal neoplasms have tumor initiating potential. Cancer Res. 2007;67:8216–8222.PubMedGoogle Scholar
  108. 108.
    Xia SJ, Barr FG. Chromosome translocations in sarcomas and the emergence of oncogenic transcription factors. Eur J Cancer. 2005;41:2513–2527.PubMedGoogle Scholar
  109. 109.
    Zoubek A, Ladenstein R, Windhager R, Amann G, Fischmeister G, Kager L, Jugovic D, Ambros PF, Gadner H, Kovar H. 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.PubMedGoogle Scholar
  110. 110.
    Zucman J, Delattre O, Desmaze C, Epstein AL, Stenman G, Speleman F, Fletchers CD, Aurias A, Thomas G. EWS and ATF-1 gene fusion induced by t(12;22) translocation in malignant melanoma of soft parts. Nat Genet. 1993;4:341–345.PubMedGoogle Scholar

Copyright information

© The Association of Bone and Joint Surgeons 2008

Authors and Affiliations

  1. 1.Department of Orthopaedic SurgeryUniversity of Minnesota—Twin CitiesMinneapolisUSA

Personalised recommendations