Skip to main navigation menu Skip to main content Skip to site footer

Review article: Biomedical intelligence

Vol. 148 No. 4748 (2018)

Synovial sarcoma: when epigenetic changes dictate tumour development

  • Nicolo Riggi
  • Luisa Cironi
  • Ivan Stamenkovic
DOI
https://doi.org/10.4414/smw.2018.14667
Cite this as:
Swiss Med Wkly. 2018;148:w14667
Published
02.12.2018

Summary

Synovial sarcoma is a highly aggressive soft tissue malignancy that often affects adolescents and young adults. It is associated with a unique chromosomal translocation that results in the formation and expression of the fusion gene SS18-SSX, which underlies its pathogenesis. Although SS18-SSX provides a potentially unique therapeutic target, all attempts to neutralise it have been unsuccessful thus far. When complete surgical removal of the tumour fails, therapy is limited to largely ineffective cytotoxic drug regimens. Nevertheless, recent discoveries about the mechanisms of SS18-SSX protein function have provided insight into potential alternative therapeutic strategies. SS18-SSX displays oncogenic activity through protein-protein interactions and participation in chromatin remodelling complexes. This review summarises our current understanding of the function of SS18-SSX and the mechanisms by which it alters the epigenetic landscape of permissive cells to induce transformation and the subsequent development of synovial sarcoma.

References

  1. Herzog CE. Overview of sarcomas in the adolescent and young adult population. J Pediatr Hematol Oncol. 2005;27(4):215–8. doi:.https://doi.org/10.1097/01.mph.0000161762.53175.e4
  2. Ladanyi M, Antonescu CR, Leung DH, Woodruff JM, Kawai A, Healey JH, et al. 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(1):135–40.
  3. Wang S, Song R, Sun T, Hou B, Hong G, Mallampati S, et al. Survival changes in Patients with Synovial Sarcoma, 1983-2012. J Cancer. 2017;8(10):1759–68. doi:.https://doi.org/10.7150/jca.17349
  4. Smith ME, Fisher C, Wilkinson LS, Edwards JC. Synovial sarcoma lack synovial differentiation. Histopathology. 1995;26(3):279–81. doi:.https://doi.org/10.1111/j.1365-2559.1995.tb01444.x
  5. Falkenstern-Ge RF, Kimmich M, Grabner A, Horn H, Friedel G, Ott G, et al. Primary pulmonary synovial sarcoma: a rare primary pulmonary tumor. Lung. 2014;192(1):211–4. doi:.https://doi.org/10.1007/s00408-013-9521-1
  6. Billings SD, Meisner LF, Cummings OW, Tejada E. Synovial sarcoma of the upper digestive tract: a report of two cases with demonstration of the X;18 translocation by fluorescence in situ hybridization. Mod Pathol. 2000;13(1):68–76. doi:.https://doi.org/10.1038/modpathol.3880011
  7. Hiraga H, Nojima T, Isu K, Yamashiro K, Yamawaki S, Nagashima K. Histological and molecular evidence of synovial sarcoma of bone. A case report. J Bone Joint Surg Am. 1999;81(4):558–63. doi:.https://doi.org/10.2106/00004623-199904000-00014
  8. Schoolmeester JK, Cheville JC, Folpe AL. Synovial sarcoma of the kidney: a clinicopathologic, immunohistochemical, and molecular genetic study of 16 cases. Am J Surg Pathol. 2014;38(1):60–5. doi:.https://doi.org/10.1097/PAS.0b013e31829b2d0d
  9. Wang JG, Li NN. Primary cardiac synovial sarcoma. Ann Thorac Surg. 2013;95(6):2202–9. doi:.https://doi.org/10.1016/j.athoracsur.2013.01.030
  10. Sultan I, Rodriguez-Galindo C, Saab R, Yasir S, Casanova M, Ferrari A. Comparing children and adults with synovial sarcoma in the Surveillance, Epidemiology, and End Results program, 1983 to 2005: an analysis of 1268 patients. Cancer. 2009;115(15):3537–47. doi:.https://doi.org/10.1002/cncr.24424
  11. Spillane AJ, A’Hern R, Judson IR, Fisher C, Thomas JM. Synovial sarcoma: a clinicopathologic, staging, and prognostic assessment. J Clin Oncol. 2000;18(22):3794–803. doi:.https://doi.org/10.1200/JCO.2000.18.22.3794
  12. Siegel HJ, Sessions W, Casillas MA, Jr, Said-Al-Naief N, Lander PH, Lopez-Ben R. Synovial sarcoma: clinicopathologic features, treatment, and prognosis. Orthopedics. 2007;30(12):1020–5, quiz 1026–7.
  13. Jaganathan S, Goyal A, Gadodia A, Rastogi S, Mittal R, Gamanagatti S. Spectrum of synovial pathologies: a pictorial assay. Curr Probl Diagn Radiol. 2012;41(1):30–42. doi:.https://doi.org/10.1067/j.cpradiol.2011.07.002
  14. Ray A, Huh WW. Current state-of-the-art systemic therapy for pediatric soft tissue sarcomas. Curr Oncol Rep. 2012;14(4):311–9. doi:.https://doi.org/10.1007/s11912-012-0243-y
  15. Bakri A, Shinagare AB, Krajewski KM, Howard SA, Jagannathan JP, Hornick JL, et al. Synovial sarcoma: imaging features of common and uncommon primary sites, metastatic patterns, and treatment response. AJR Am J Roentgenol. 2012;199(2):W208–15. doi:.https://doi.org/10.2214/AJR.11.8039
  16. Ferrari A, De Salvo GL, Oberlin O, Casanova M, De Paoli A, Rey A, et al. Synovial sarcoma in children and adolescents: a critical reappraisal of staging investigations in relation to the rate of metastatic involvement at diagnosis. Eur J Cancer. 2012;48(9):1370–5. doi:.https://doi.org/10.1016/j.ejca.2012.01.013
  17. Dantonello TM, Int-Veen C, Harms D, Leuschner I, Schmidt BF, Herbst M, et al. Cooperative trial CWS-91 for localized soft tissue sarcoma in children, adolescents, and young adults. J Clin Oncol. 2009;27(9):1446–55. doi:.https://doi.org/10.1200/JCO.2007.15.0466
  18. Riggi N, Cironi L, Suvà ML, Stamenkovic I. Sarcomas: genetics, signalling, and cellular origins. Part 1: The fellowship of TET. J Pathol. 2007;213(1):4–20. doi:.https://doi.org/10.1002/path.2209
  19. Folpe AL, Schmidt RA, Chapman D, Gown AM. Poorly differentiated synovial sarcoma: immunohistochemical distinction from primitive neuroectodermal tumors and high-grade malignant peripheral nerve sheath tumors. Am J Surg Pathol. 1998;22(6):673–82. doi:.https://doi.org/10.1097/00000478-199806000-00004
  20. Sato O, Wada T, Kawai A, Yamaguchi U, Makimoto A, Kokai Y, et al. Expression of epidermal growth factor receptor, ERBB2 and KIT in adult soft tissue sarcomas: a clinicopathologic study of 281 cases. Cancer. 2005;103(9):1881–90. doi:.https://doi.org/10.1002/cncr.20986
  21. Fleuren EDG, Vlenterie M, van der Graaf WTA, Hillebrandt-Roeffen MHS, Blackburn J, Ma X, et al. Phosphoproteomic Profiling Reveals ALK and MET as Novel Actionable Targets across Synovial Sarcoma Subtypes. Cancer Res. 2017;77(16):4279–92. doi:.https://doi.org/10.1158/0008-5472.CAN-16-2550
  22. Yamada S, Imura Y, Nakai T, Nakai S, Yasuda N, Kaneko K, et al. Therapeutic potential of TAS-115 via c-MET and PDGFRα signal inhibition for synovial sarcoma. BMC Cancer. 2017;17(1):334. doi:.https://doi.org/10.1186/s12885-017-3324-3
  23. Imura Y, Nakai T, Yamada S, Outani H, Takenaka S, Hamada K, et al. Functional and therapeutic relevance of hepatocyte growth factor/c-MET signaling in synovial sarcoma. Cancer Sci. 2016;107(12):1867–76. doi:.https://doi.org/10.1111/cas.13092
  24. Clark J, Rocques PJ, Crew AJ, Gill S, Shipley J, Chan AM, et al. Identification of novel genes, SYT and SSX, involved in the t(X;18)(p11.2;q11.2) translocation found in human synovial sarcoma. Nat Genet. 1994;7(4):502–8. doi:.https://doi.org/10.1038/ng0894-502
  25. Skytting B, Nilsson G, Brodin B, Xie Y, Lundeberg J, Uhlén M, et al. A novel fusion gene, SYT-SSX4, in synovial sarcoma. J Natl Cancer Inst. 1999;91(11):974–5. doi:.https://doi.org/10.1093/jnci/91.11.974
  26. Panagopoulos I, Mertens F, Isaksson M, Limon J, Gustafson P, Skytting B, et al. Clinical impact of molecular and cytogenetic findings in synovial sarcoma. Genes Chromosomes Cancer. 2001;31(4):362–72. doi:.https://doi.org/10.1002/gcc.1155
  27. Joseph CG, Hwang H, Jiao Y, Wood LD, Kinde I, Wu J, et al. Exomic analysis of myxoid liposarcomas, synovial sarcomas, and osteosarcomas. Genes Chromosomes Cancer. 2014;53(1):15–24. doi:.https://doi.org/10.1002/gcc.22114
  28. 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(4):375–88. doi:.https://doi.org/10.1016/j.ccr.2007.01.016
  29. Carmody Soni EE, Schlottman S, Erkizan HV, Uren A, Toretsky JA. Loss of SS18-SSX1 inhibits viability and induces apoptosis in synovial sarcoma. Clin Orthop Relat Res. 2014;472(3):874–82. doi:.https://doi.org/10.1007/s11999-013-3065-9
  30. Haldar M, Hedberg ML, Hockin MF, Capecchi MR. A CreER-based random induction strategy for modeling translocation-associated sarcomas in mice. Cancer Res. 2009;69(8):3657–64. doi:.https://doi.org/10.1158/0008-5472.CAN-08-4127
  31. Cironi L, Petricevic T, Fernandes Vieira V, Provero P, Fusco C, Cornaz S, et al. The fusion protein SS18-SSX1 employs core Wnt pathway transcription factors to induce a partial Wnt signature in synovial sarcoma. Sci Rep. 2016;6(1):22113. doi:.https://doi.org/10.1038/srep22113
  32. Naka N, Takenaka S, Araki N, Miwa T, Hashimoto N, Yoshioka K, et al. Synovial sarcoma is a stem cell malignancy. Stem Cells. 2010;28(7):1119–31.
  33. Cironi L, Provero P, Riggi N, Janiszewska M, Suva D, Suva ML, et al. Epigenetic features of human mesenchymal stem cells determine their permissiveness for induction of relevant transcriptional changes by SYT-SSX1. PLoS One. 2009;4(11):e7904. doi:.https://doi.org/10.1371/journal.pone.0007904
  34. Dominici M, Le Blanc K, Mueller I, Slaper-Cortenbach I, Marini F, Krause D, et al. Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement. Cytotherapy. 2006;8(4):315–7. doi:.https://doi.org/10.1080/14653240600855905
  35. Riggi N, Cironi L, Provero P, Suvà ML, Kaloulis K, Garcia-Echeverria C, et al. Development of Ewing’s sarcoma from primary bone marrow-derived mesenchymal progenitor cells. Cancer Res. 2005;65(24):11459–68. doi:.https://doi.org/10.1158/0008-5472.CAN-05-1696
  36. Riggi N, Cironi L, Provero P, Suvà ML, Stehle JC, Baumer K, et al. Expression of the FUS-CHOP fusion protein in primary mesenchymal progenitor cells gives rise to a model of myxoid liposarcoma. Cancer Res. 2006;66(14):7016–23. doi:.https://doi.org/10.1158/0008-5472.CAN-05-3979
  37. Galland S, Vuille J, Martin P, Letovanec I, Caignard A, Fregni G, et al. Tumor-Derived Mesenchymal Stem Cells Use Distinct Mechanisms to Block the Activity of Natural Killer Cell Subsets. Cell Reports. 2017;20(12):2891–905. doi:.https://doi.org/10.1016/j.celrep.2017.08.089
  38. Liu A, Feng B, Gu W, Cheng X, Tong T, Zhang H, et al. The CD133+ subpopulation of the SW982 human synovial sarcoma cell line exhibits cancer stem-like characteristics. Int J Oncol. 2013;42(4):1399–407. doi:.https://doi.org/10.3892/ijo.2013.1826
  39. Kimura T, Wang L, Tabu K, Tsuda M, Tanino M, Maekawa A, et al. Identification and analysis of CXCR4-positive synovial sarcoma-initiating cells. Oncogene. 2016;35(30):3932–43. doi:.https://doi.org/10.1038/onc.2015.461
  40. de Bruijn DR, Baats E, Zechner U, de Leeuw B, Balemans M, Olde Weghuis D, et al. Isolation and characterization of the mouse homolog of SYT, a gene implicated in the development of human synovial sarcomas. Oncogene. 1996;13(3):643–8.
  41. Brett D, Whitehouse S, Antonson P, Shipley J, Cooper C, Goodwin G. The SYT protein involved in the t(X;18) synovial sarcoma translocation is a transcriptional activator localised in nuclear bodies. Hum Mol Genet. 1997;6(9):1559–64. doi:.https://doi.org/10.1093/hmg/6.9.1559
  42. Middeljans E, Wan X, Jansen PW, Sharma V, Stunnenberg HG, Logie C. SS18 together with animal-specific factors defines human BAF-type SWI/SNF complexes. PLoS One. 2012;7(3):e33834. doi:.https://doi.org/10.1371/journal.pone.0033834
  43. Thaete C, Brett D, Monaghan P, Whitehouse S, Rennie G, Rayner E, et al. Functional domains of the SYT and SYT-SSX synovial sarcoma translocation proteins and co-localization with the SNF protein BRM in the nucleus. Hum Mol Genet. 1999;8(4):585–91. doi:.https://doi.org/10.1093/hmg/8.4.585
  44. Kato H, Tjernberg A, Zhang W, Krutchinsky AN, An W, Takeuchi T, et al. SYT associates with human SNF/SWI complexes and the C-terminal region of its fusion partner SSX1 targets histones. J Biol Chem. 2002;277(7):5498–505. doi:.https://doi.org/10.1074/jbc.M108702200
  45. Suvà ML, Riggi N, Bernstein BE. Epigenetic reprogramming in cancer. Science. 2013;339(6127):1567–70. doi:.https://doi.org/10.1126/science.1230184
  46. Dawson MA, Kouzarides T. Cancer epigenetics: from mechanism to therapy. Cell. 2012;150(1):12–27. doi:.https://doi.org/10.1016/j.cell.2012.06.013
  47. Mueller-Planitz F, Klinker H, Becker PB. Nucleosome sliding mechanisms: new twists in a looped history. Nat Struct Mol Biol. 2013;20(9):1026–32. doi:.https://doi.org/10.1038/nsmb.2648
  48. St. Pierre R, Kadoch C. Mammalian SWI/SNF complexes in cancer: emerging therapeutic opportunities. Curr Opin Genet Dev. 2017;42:56–67. doi:.https://doi.org/10.1016/j.gde.2017.02.004
  49. Masliah-Planchon J, Bièche I, Guinebretière JM, Bourdeaut F, Delattre O. SWI/SNF chromatin remodeling and human malignancies. Annu Rev Pathol. 2015;10(1):145–71. doi:.https://doi.org/10.1146/annurev-pathol-012414-040445
  50. Zöllner SK, Rössig C, Toretsky JA. Synovial sarcoma is a gateway to the role of chromatin remodeling in cancer. Cancer Metastasis Rev. 2015;34(3):417–28. doi:.https://doi.org/10.1007/s10555-015-9575-z
  51. Wang W, Xue Y, Zhou S, Kuo A, Cairns BR, Crabtree GR. Diversity and specialization of mammalian SWI/SNF complexes. Genes Dev. 1996;10(17):2117–30. doi:.https://doi.org/10.1101/gad.10.17.2117
  52. Perani M, Ingram CJ, Cooper CS, Garrett MD, Goodwin GH. Conserved SNH domain of the proto-oncoprotein SYT interacts with components of the human chromatin remodelling complexes, while the QPGY repeat domain forms homo-oligomers. Oncogene. 2003;22(50):8156–67. doi:.https://doi.org/10.1038/sj.onc.1207031
  53. Kadoch C, Crabtree GR. Reversible disruption of mSWI/SNF (BAF) complexes by the SS18-SSX oncogenic fusion in synovial sarcoma. Cell. 2013;153(1):71–85. doi:.https://doi.org/10.1016/j.cell.2013.02.036
  54. Ito T, Ouchida M, Ito S, Jitsumori Y, Morimoto Y, Ozaki T, et al. SYT, a partner of SYT-SSX oncoprotein in synovial sarcomas, interacts with mSin3A, a component of histone deacetylase complex. Lab Invest. 2004;84(11):1484–90. doi:.https://doi.org/10.1038/labinvest.3700174
  55. Dufau ML, Liao M, Zhang Y. Participation of signaling pathways in the derepression of luteinizing hormone receptor transcription. Mol Cell Endocrinol. 2010;314(2):221–7. doi:.https://doi.org/10.1016/j.mce.2009.05.005
  56. Silverstein RA, Ekwall K. Sin3: a flexible regulator of global gene expression and genome stability. Curr Genet. 2005;47(1):1–17. doi:.https://doi.org/10.1007/s00294-004-0541-5
  57. Nan X, Ng HH, Johnson CA, Laherty CD, Turner BM, Eisenman RN, et al. Transcriptional repression by the methyl-CpG-binding protein MeCP2 involves a histone deacetylase complex. Nature. 1998;393(6683):386–9. doi:.https://doi.org/10.1038/30764
  58. Bannister AJ, Kouzarides T. The CBP co-activator is a histone acetyltransferase. Nature. 1996;384(6610):641–3. doi:.https://doi.org/10.1038/384641a0
  59. Ogryzko VV, Schiltz RL, Russanova V, Howard BH, Nakatani Y. The transcriptional coactivators p300 and CBP are histone acetyltransferases. Cell. 1996;87(5):953–9. doi:.https://doi.org/10.1016/S0092-8674(00)82001-2
  60. Eid JE, Kung AL, Scully R, Livingston DM. p300 interacts with the nuclear proto-oncoprotein SYT as part of the active control of cell adhesion. Cell. 2000;102(6):839–48. doi:.https://doi.org/10.1016/S0092-8674(00)00072-6
  61. Perani M, Antonson P, Hamoudi R, Ingram CJ, Cooper CS, Garrett MD, et al. The proto-oncoprotein SYT interacts with SYT-interacting protein/co-activator activator (SIP/CoAA), a human nuclear receptor co-activator with similarity to EWS and TLS/FUS family of proteins. J Biol Chem. 2005;280(52):42863–76. doi:.https://doi.org/10.1074/jbc.M502963200
  62. Iwasaki T, Chin WW, Ko L. Identification and characterization of RRM-containing coactivator activator (CoAA) as TRBP-interacting protein, and its splice variant as a coactivator modulator (CoAM). J Biol Chem. 2001;276(36):33375–83. doi:.https://doi.org/10.1074/jbc.M101517200
  63. Güre AO, Wei IJ, Old LJ, Chen YT. The SSX gene family: characterization of 9 complete genes. Int J Cancer. 2002;101(5):448–53. doi:.https://doi.org/10.1002/ijc.10634
  64. Gure AO, Türeci O, Sahin U, Tsang S, Scanlan MJ, Jäger E, et al. SSX: a multigene family with several members transcribed in normal testis and human cancer. Int J Cancer. 1997;72(6):965–71. doi:.https://doi.org/10.1002/(SICI)1097-0215(19970917)72:6<965::AID-IJC8>3.0.CO;2-N
  65. de Bruijn DR, van Dijk AH, Willemse MP, van Kessel AG. The C terminus of the synovial sarcoma-associated SSX proteins interacts with the LIM homeobox protein LHX4. Oncogene. 2008;27(5):653–62. doi:.https://doi.org/10.1038/sj.onc.1210688
  66. dos Santos NR, Torensma R, de Vries TJ, Schreurs MW, de Bruijn DR, Kater-Baats E, et al. Heterogeneous expression of the SSX cancer/testis antigens in human melanoma lesions and cell lines. Cancer Res. 2000;60(6):1654–62.
  67. Mischo A, Kubuschok B, Ertan K, Preuss KD, Romeike B, Regitz E, et al. Prospective study on the expression of cancer testis genes and antibody responses in 100 consecutive patients with primary breast cancer. Int J Cancer. 2006;118(3):696–703. doi:.https://doi.org/10.1002/ijc.21352
  68. Naka N, Araki N, Nakanishi H, Itoh K, Mano M, Ishiguro S, et al. Expression of SSX genes in human osteosarcomas. Int J Cancer. 2002;98(4):640–2. doi:.https://doi.org/10.1002/ijc.10277
  69. dos Santos NR, de Bruijn DR, van Kessel AG. Molecular mechanisms underlying human synovial sarcoma development. Genes Chromosomes Cancer. 2001;30(1):1–14. doi:.https://doi.org/10.1002/1098-2264(2000)9999:9999<::AID-GCC1056>3.0.CO;2-G
  70. Taylor BJ, Reiman T, Pittman JA, Keats JJ, de Bruijn DR, Mant MJ, et al. SSX cancer testis antigens are expressed in most multiple myeloma patients: co-expression of SSX1, 2, 4, and 5 correlates with adverse prognosis and high frequencies of SSX-positive PCs. J Immunother. 2005;28(6):564–75. doi:.https://doi.org/10.1097/01.cji.0000175685.36239.e5
  71. dos Santos NR, de Bruijn DR, Kater-Baats E, Otte AP, van Kessel AG. Delineation of the protein domains responsible for SYT, SSX, and SYT-SSX nuclear localization. Exp Cell Res. 2000;256(1):192–202. doi:.https://doi.org/10.1006/excr.2000.4813
  72. Francis NJ, Kingston RE, Woodcock CL. Chromatin compaction by a polycomb group protein complex. Science. 2004;306(5701):1574–7. doi:.https://doi.org/10.1126/science.1100576
  73. Sauvageau M, Sauvageau G. Polycomb group proteins: multi-faceted regulators of somatic stem cells and cancer. Cell Stem Cell. 2010;7(3):299–313. doi:.https://doi.org/10.1016/j.stem.2010.08.002
  74. Margueron R, Reinberg D. The Polycomb complex PRC2 and its mark in life. Nature. 2011;469(7330):343–9. doi:.https://doi.org/10.1038/nature09784
  75. Wang J, Wang H, Hou W, Liu H, Zou Y, Zhang H, et al. Subnuclear distribution of SSX regulates its function. Mol Cell Biochem. 2013;381(1-2):17–29. doi:.https://doi.org/10.1007/s11010-013-1684-9
  76. de Bruijn DR, dos Santos NR, Kater-Baats E, Thijssen J, van den Berk L, Stap J, et al. The cancer-related protein SSX2 interacts with the human homologue of a Ras-like GTPase interactor, RAB3IP, and a novel nuclear protein, SSX2IP. Genes Chromosomes Cancer. 2002;34(3):285–98. doi:.https://doi.org/10.1002/gcc.10073
  77. Kawamata N, Sakajiri S, Sugimoto KJ, Isobe Y, Kobayashi H, Oshimi K. A novel chromosomal translocation t(1;14)(q25;q32) in pre-B acute lymphoblastic leukemia involves the LIM homeodomain protein gene, Lhx4. Oncogene. 2002;21(32):4983–91. doi:.https://doi.org/10.1038/sj.onc.1205628
  78. Saito T, Nagai M, Ladanyi M. SYT-SSX1 and SYT-SSX2 interfere with repression of E-cadherin by snail and slug: a potential mechanism for aberrant mesenchymal to epithelial transition in human synovial sarcoma. Cancer Res. 2006;66(14):6919–27. doi:.https://doi.org/10.1158/0008-5472.CAN-05-3697
  79. Nagai M, Tanaka S, Tsuda M, Endo S, Kato H, Sonobe H, et al. Analysis of transforming activity of human synovial sarcoma-associated chimeric protein SYT-SSX1 bound to chromatin remodeling factor hBRM/hSNF2 alpha. Proc Natl Acad Sci USA. 2001;98(7):3843–8. doi:.https://doi.org/10.1073/pnas.061036798
  80. Soulez M, Saurin AJ, Freemont PS, Knight JC. SSX and the synovial-sarcoma-specific chimaeric protein SYT-SSX co-localize with the human Polycomb group complex. Oncogene. 1999;18(17):2739–46. doi:.https://doi.org/10.1038/sj.onc.1202613
  81. Garcia CB, Shaffer CM, Eid JE. Genome-wide recruitment to Polycomb-modified chromatin and activity regulation of the synovial sarcoma oncogene SYT-SSX2. BMC Genomics. 2012;13(1):189. doi:.https://doi.org/10.1186/1471-2164-13-189
  82. Lubieniecka JM, de Bruijn DR, Su L, van Dijk AH, Subramanian S, van de Rijn M, et al. Histone deacetylase inhibitors reverse SS18-SSX-mediated polycomb silencing of the tumor suppressor early growth response 1 in synovial sarcoma. Cancer Res. 2008;68(11):4303–10. doi:.https://doi.org/10.1158/0008-5472.CAN-08-0092
  83. Changchien YC, Tátrai P, Papp G, Sápi J, Fónyad L, Szendrői M, et al. Poorly differentiated synovial sarcoma is associated with high expression of enhancer of zeste homologue 2 (EZH2). J Transl Med. 2012;10(1):216. doi:.https://doi.org/10.1186/1479-5876-10-216
  84. Mousavi K, Zare H, Wang AH, Sartorelli V. Polycomb protein Ezh1 promotes RNA polymerase II elongation. Mol Cell. 2012;45(2):255–62. doi:.https://doi.org/10.1016/j.molcel.2011.11.019
  85. Wilson BG, Wang X, Shen X, McKenna ES, Lemieux ME, Cho YJ, et al. Epigenetic antagonism between polycomb and SWI/SNF complexes during oncogenic transformation. Cancer Cell. 2010;18(4):316–28. doi:.https://doi.org/10.1016/j.ccr.2010.09.006
  86. Kadoch C, Williams RT, Calarco JP, Miller EL, Weber CM, Braun SM, et al. Dynamics of BAF-Polycomb complex opposition on heterochromatin in normal and oncogenic states. Nat Genet. 2017;49(2):213–22. doi:.https://doi.org/10.1038/ng.3734
  87. Su L, Sampaio AV, Jones KB, Pacheco M, Goytain A, Lin S, et al. Deconstruction of the SS18-SSX fusion oncoprotein complex: insights into disease etiology and therapeutics. Cancer Cell. 2012;21(3):333–47. doi:.https://doi.org/10.1016/j.ccr.2012.01.010
  88. Pretto D, Barco R, Rivera J, Neel N, Gustavson MD, Eid JE. The synovial sarcoma translocation protein SYT-SSX2 recruits beta-catenin to the nucleus and associates with it in an active complex. Oncogene. 2006;25(26):3661–9. doi:.https://doi.org/10.1038/sj.onc.1209413
  89. Fukukawa C, Nagayama S, Tsunoda T, Toguchida J, Nakamura Y, Katagiri T. Activation of the non-canonical Dvl-Rac1-JNK pathway by Frizzled homologue 10 in human synovial sarcoma. Oncogene. 2009;28(8):1110–20. doi:.https://doi.org/10.1038/onc.2008.467
  90. Trautmann M, Sievers E, Aretz S, Kindler D, Michels S, Friedrichs N, et al. SS18-SSX fusion protein-induced Wnt/β-catenin signaling is a therapeutic target in synovial sarcoma. Oncogene. 2014;33(42):5006–16. doi:.https://doi.org/10.1038/onc.2013.443
  91. Cadigan KM, Peifer M. Wnt signaling from development to disease: insights from model systems. Cold Spring Harb Perspect Biol. 2009;1(2):a002881. doi:.https://doi.org/10.1101/cshperspect.a002881
  92. MacDonald BT, Tamai K, He X. Wnt/beta-catenin signaling: components, mechanisms, and diseases. Dev Cell. 2009;17(1):9–26. doi:.https://doi.org/10.1016/j.devcel.2009.06.016
  93. Clevers H, Nusse R. Wnt/β-catenin signaling and disease. Cell. 2012;149(6):1192–205. doi:.https://doi.org/10.1016/j.cell.2012.05.012
  94. Logan CY, Nusse R. The Wnt signaling pathway in development and disease. Annu Rev Cell Dev Biol. 2004;20(1):781–810. doi:.https://doi.org/10.1146/annurev.cellbio.20.010403.113126
  95. Polakis P. Wnt signaling and cancer. Genes Dev. 2000;14(15):1837–51.
  96. Reya T, Clevers H. Wnt signalling in stem cells and cancer. Nature. 2005;434(7035):843–50. doi:.https://doi.org/10.1038/nature03319
  97. Barham W, Frump AL, Sherrill TP, Garcia CB, Saito-Diaz K, VanSaun MN, et al. Targeting the Wnt pathway in synovial sarcoma models. Cancer Discov. 2013;3(11):1286–301. doi:.https://doi.org/10.1158/2159-8290.CD-13-0138
  98. Saito T, Oda Y, Sakamoto A, Tamiya S, Kinukawa N, Hayashi K, et al. Prognostic value of the preserved expression of the E-cadherin and catenin families of adhesion molecules and of beta-catenin mutations in synovial sarcoma. J Pathol. 2000;192(3):342–50. doi:.https://doi.org/10.1002/1096-9896(2000)9999:9999<::AID-PATH705>3.0.CO;2-R
  99. Ng TL, Gown AM, Barry TS, Cheang MC, Chan AK, Turbin DA, et al. Nuclear beta-catenin in mesenchymal tumors. Mod Pathol. 2005;18(1):68–74. doi:.https://doi.org/10.1038/modpathol.3800272
  100. Saito T, Oda Y, Sakamoto A, Kawaguchi K, Tanaka K, Matsuda S, et al. APC mutations in synovial sarcoma. J Pathol. 2002;196(4):445–9. doi:.https://doi.org/10.1002/path.1066
  101. Horvai AE, Kramer MJ, O’Donnell R. Beta-catenin nuclear expression correlates with cyclin D1 expression in primary and metastatic synovial sarcoma: a tissue microarray study. Arch Pathol Lab Med. 2006;130(6):792–8.
  102. Saito T, Oda Y, Yamamoto H, Kawaguchi K, Tanaka K, Matsuda S, et al. Nuclear beta-catenin correlates with cyclin D1 expression in spindle and pleomorphic sarcomas but not in synovial sarcoma. Hum Pathol. 2006;37(6):689–97. doi:.https://doi.org/10.1016/j.humpath.2006.01.017
  103. Sato H, Hasegawa T, Kanai Y, Tsutsumi Y, Osamura Y, Abe Y, et al. Expression of cadherins and their undercoat proteins (alpha-, beta-, and gamma-catenins and p120) and accumulation of beta-catenin with no gene mutations in synovial sarcoma. Virchows Arch. 2001;438(1):23–30. doi:.https://doi.org/10.1007/s004280000318
  104. Antonescu CR, Kawai A, Leung DH, Lonardo F, Woodruff JM, Healey JH, et al. Strong association of SYT-SSX fusion type and morphologic epithelial differentiation in synovial sarcoma. Diagn Mol Pathol. 2000;9(1):1–8. doi:.https://doi.org/10.1097/00019606-200003000-00001
  105. 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(3):153–60. doi:.https://doi.org/10.1056/NEJM199801153380303
  106. Saito T, Oda Y, Kawaguchi K, Sugimachi K, Yamamoto H, Tateishi N, et al. E-cadherin mutation and Snail overexpression as alternative mechanisms of E-cadherin inactivation in synovial sarcoma. Oncogene. 2004;23(53):8629–38. doi:.https://doi.org/10.1038/sj.onc.1207960
  107. Saito T, Oda Y, Sugimachi K, Kawaguchi K, Tamiya S, Tanaka K, et al. E-cadherin gene mutations frequently occur in synovial sarcoma as a determinant of histological features. Am J Pathol. 2001;159(6):2117–24. doi:.https://doi.org/10.1016/S0002-9440(10)63063-5
  108. Saito T. The SYT-SSX fusion protein and histological epithelial differentiation in synovial sarcoma: relationship with extracellular matrix remodeling. Int J Clin Exp Pathol. 2013;6(11):2272–9.