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Pathogenetic factors in soft tissue and bone sarcomas

Thomas F DeLaney, MD
David G Kirsch, MD, PhD
Section Editors
Robert Maki, MD, PhD
Raphael E Pollock, MD
Deputy Editor
Diane MF Savarese, MD


Sarcomas are malignant tumors arising from skeletal and extraskeletal connective tissues, including the peripheral nervous system. Approximately 76 percent arise in soft tissue, the remainder in bone.

There is no clearly defined etiology in most cases of soft tissue sarcoma, but a number of associated or predisposing factors have been identified [1]. These include a genetic predisposition, gene mutations, radiation therapy (RT), chemotherapy, chemical carcinogens, chronic irritation, and lymphedema. In addition, an association between viral infection and sarcoma has been shown for HIV and human herpesvirus 8 in Kaposi sarcoma, and for Epstein-Barr virus (EBV) and smooth muscle tumors in immunocompromised patients.


Some patients with bone and soft tissue sarcomas, particularly children, have a genetic predisposition to cancer [1-5]. In some cases, individuals are from families with a defined inherited predisposing condition, such as Li-Fraumeni syndrome (LFS) or retinoblastoma, but many cases do not fit recognized inherited cancer syndromes. One analysis, in which 1162 patients with sarcoma, unselected for family history, underwent targeted exon sequencing of 72 genes selected for their association with cancer risk, concluded that approximately one-half of the patients had putatively pathogenic, monogenic, and polygenic variation in known and novel cancer genes [6]. In a pooled analysis of all sarcoma probands, 240 carried multiple variants, suggesting a polygenic contribution to sarcoma risk. Only 155 (17 percent) of the 911 families with informative pedigrees fit recognizable cancer syndromes.

The major genetic syndromes are briefly outlined below.

Li-Fraumeni syndrome — Mutations in TP53 are the most common germline mutations that predispose to pediatric sarcomas, including osteosarcoma, rhabdomyosarcoma, and Ewing sarcoma [5]. As many as 7 percent of children with soft tissue sarcomas may have LFS [7]. In a series of 151 children with soft tissue sarcomas, for example, five of the families (3.3 percent) manifested the classic LFS familial cancer syndrome, 10 (6.6 percent) had features consistent with the syndrome, and 16 (10.5 percent) had one parent with a possible hereditary cancer syndrome or with cancer before the age of 60 [4].

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Literature review current through: Nov 2017. | This topic last updated: Jun 08, 2017.
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  1. Zahm SH, Fraumeni JF Jr. The epidemiology of soft tissue sarcoma. Semin Oncol 1997; 24:504.
  2. Li FP. Cancer families: human models of susceptibility to neoplasia--the Richard and Hinda Rosenthal Foundation Award lecture. Cancer Res 1988; 48:5381.
  3. Li FP, Fraumeni JF Jr, Mulvihill JJ, et al. A cancer family syndrome in twenty-four kindreds. Cancer Res 1988; 48:5358.
  4. Hartley AL, Birch JM, Blair V, et al. Patterns of cancer in the families of children with soft tissue sarcoma. Cancer 1993; 72:923.
  5. Zhang J, Walsh MF, Wu G, et al. Germline Mutations in Predisposition Genes in Pediatric Cancer. N Engl J Med 2015; 373:2336.
  6. Ballinger ML, Goode DL, Ray-Coquard I, et al. Monogenic and polygenic determinants of sarcoma risk: an international genetic study. Lancet Oncol 2016; 17:1261.
  7. Carnevale A, Lieberman E, Cárdenas R. Li-Fraumeni syndrome in pediatric patients with soft tissue sarcoma or osteosarcoma. Arch Med Res 1997; 28:383.
  8. Evans SC, Lozano G. The Li-Fraumeni syndrome: an inherited susceptibility to cancer. Mol Med Today 1997; 3:390.
  9. Varley JM, McGown G, Thorncroft M, et al. Germ-line mutations of TP53 in Li-Fraumeni families: an extended study of 39 families. Cancer Res 1997; 57:3245.
  10. Malkin D. p53 and the Li-Fraumeni syndrome. Cancer Genet Cytogenet 1993; 66:83.
  11. Mai PL, Best AF, Peters JA, et al. Risks of first and subsequent cancers among TP53 mutation carriers in the National Cancer Institute Li-Fraumeni syndrome cohort. Cancer 2016; 122:3673.
  12. Ognjanovic S, Olivier M, Bergemann TL, Hainaut P. Sarcomas in TP53 germline mutation carriers: a review of the IARC TP53 database. Cancer 2012; 118:1387.
  13. Hizawa K, Iida M, Mibu R, et al. Desmoid tumors in familial adenomatous polyposis/Gardner's syndrome. J Clin Gastroenterol 1997; 25:334.
  14. DerKinderen DJ, Koten JW, Nagelkerke NJ, et al. Non-ocular cancer in patients with hereditary retinoblastoma and their relatives. Int J Cancer 1988; 41:499.
  15. Kleinerman RA, Tucker MA, Tarone RE, et al. Risk of new cancers after radiotherapy in long-term survivors of retinoblastoma: an extended follow-up. J Clin Oncol 2005; 23:2272.
  16. Yu CL, Tucker MA, Abramson DH, et al. Cause-specific mortality in long-term survivors of retinoblastoma. J Natl Cancer Inst 2009; 101:581.
  17. Kleinerman RA, Tucker MA, Abramson DH, et al. Risk of soft tissue sarcomas by individual subtype in survivors of hereditary retinoblastoma. J Natl Cancer Inst 2007; 99:24.
  18. Brekke HR, Ribeiro FR, Kolberg M, et al. Genomic changes in chromosomes 10, 16, and X in malignant peripheral nerve sheath tumors identify a high-risk patient group. J Clin Oncol 2010; 28:1573.
  19. Mertens F, Rydholm A, Bauer HF, et al. Cytogenetic findings in malignant peripheral nerve sheath tumors. Int J Cancer 1995; 61:793.
  20. Ducatman BS, Scheithauer BW, Piepgras DG, et al. Malignant peripheral nerve sheath tumors. A clinicopathologic study of 120 cases. Cancer 1986; 57:2006.
  21. Borden EC, Baker LH, Bell RS, et al. Soft tissue sarcomas of adults: state of the translational science. Clin Cancer Res 2003; 9:1941.
  22. Italiano A, Di Mauro I, Rapp J, et al. Clinical effect of molecular methods in sarcoma diagnosis (GENSARC): a prospective, multicentre, observational study. Lancet Oncol 2016; 17:532.
  23. Ladanyi M, Bridge JA. Contribution of molecular genetic data to the classification of sarcomas. Hum Pathol 2000; 31:532.
  24. Mohamed AN, Zalupski MM, Ryan JR, et al. Cytogenetic aberrations and DNA ploidy in soft tissue sarcoma. A Southwest Oncology Group Study. Cancer Genet Cytogenet 1997; 99:45.
  25. Barretina J, Taylor BS, Banerji S, et al. Subtype-specific genomic alterations define new targets for soft-tissue sarcoma therapy. Nat Genet 2010; 42:715.
  26. Italiano A, Bianchini L, Keslair F, et al. HMGA2 is the partner of MDM2 in well-differentiated and dedifferentiated liposarcomas whereas CDK4 belongs to a distinct inconsistent amplicon. Int J Cancer 2008; 122:2233.
  27. Chen X, Stewart E, Shelat AA, et al. Targeting oxidative stress in embryonal rhabdomyosarcoma. Cancer Cell 2013; 24:710.
  28. Shern JF, Chen L, Chmielecki J, et al. Comprehensive genomic analysis of rhabdomyosarcoma reveals a landscape of alterations affecting a common genetic axis in fusion-positive and fusion-negative tumors. Cancer Discov 2014; 4:216.
  29. Zhang M, Linardic CM, Kirsch DG. RAS and ROS in rhabdomyosarcoma. Cancer Cell 2013; 24:689.
  30. Martin GA, Viskochil D, Bollag G, et al. The GAP-related domain of the neurofibromatosis type 1 gene product interacts with ras p21. Cell 1990; 63:843.
  31. Xu GF, Lin B, Tanaka K, et al. The catalytic domain of the neurofibromatosis type 1 gene product stimulates ras GTPase and complements ira mutants of S. cerevisiae. Cell 1990; 63:835.
  32. Lee W, Teckie S, Wiesner T, et al. PRC2 is recurrently inactivated through EED or SUZ12 loss in malignant peripheral nerve sheath tumors. Nat Genet 2014; 46:1227.
  33. De Raedt T, Beert E, Pasmant E, et al. PRC2 loss amplifies Ras-driven transcription and confers sensitivity to BRD4-based therapies. Nature 2014; 514:247.
  34. el-Deiry WS, Tokino T, Velculescu VE, et al. WAF1, a potential mediator of p53 tumor suppression. Cell 1993; 75:817.
  35. Lane DP. Cancer. p53, guardian of the genome. Nature 1992; 358:15.
  36. Levine AJ, Perry ME, Chang A, et al. The 1993 Walter Hubert Lecture: the role of the p53 tumour-suppressor gene in tumorigenesis. Br J Cancer 1994; 69:409.
  37. Toguchida J, Yamaguchi T, Dayton SH, et al. Prevalence and spectrum of germline mutations of the p53 gene among patients with sarcoma. N Engl J Med 1992; 326:1301.
  38. Malkin D, Jolly KW, Barbier N, et al. Germline mutations of the p53 tumor-suppressor gene in children and young adults with second malignant neoplasms. N Engl J Med 1992; 326:1309.
  39. McIntyre JF, Smith-Sorensen B, Friend SH, et al. Germline mutations of the p53 tumor suppressor gene in children with osteosarcoma. J Clin Oncol 1994; 12:925.
  40. Vogel KS, Klesse LJ, Velasco-Miguel S, et al. Mouse tumor model for neurofibromatosis type 1. Science 1999; 286:2176.
  41. Toguchida J, Yamaguchi T, Ritchie B, et al. Mutation spectrum of the p53 gene in bone and soft tissue sarcomas. Cancer Res 1992; 52:6194.
  42. 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.
  43. Porter PL, Gown AM, Kramp SG, Coltrera MD. Widespread p53 overexpression in human malignant tumors. An immunohistochemical study using methacarn-fixed, embedded tissue. Am J Pathol 1992; 140:145.
  44. Soini Y, Vähäkangas K, Nuorva K, et al. p53 immunohistochemistry in malignant fibrous histiocytomas and other mesenchymal tumours. J Pathol 1992; 168:29.
  45. Stratton MR, Moss S, Warren W, et al. Mutation of the p53 gene in human soft tissue sarcomas: association with abnormalities of the RB1 gene. Oncogene 1990; 5:1297.
  46. Mulligan LM, Matlashewski GJ, Scrable HJ, Cavenee WK. Mechanisms of p53 loss in human sarcomas. Proc Natl Acad Sci U S A 1990; 87:5863.
  47. Patterson H, Gill S, Fisher C, et al. Abnormalities of the p53 MDM2 and DCC genes in human leiomyosarcomas. Br J Cancer 1994; 69:1052.
  48. Andreassen A, Oyjord T, Hovig E, et al. p53 abnormalities in different subtypes of human sarcomas. Cancer Res 1993; 53:468.
  49. Blom R, Guerrieri C, Stâl O, et al. Leiomyosarcoma of the uterus: A clinicopathologic, DNA flow cytometric, p53, and mdm-2 analysis of 49 cases. Gynecol Oncol 1998; 68:54.
  50. Simms WW, Ordóñez NG, Johnston D, et al. p53 expression in dedifferentiated chondrosarcoma. Cancer 1995; 76:223.
  51. Pollock RE, Lang A, Luo J, et al. Soft tissue sarcoma metastasis from clonal expansion of p53 mutated tumor cells. Oncogene 1996; 12:2035.
  52. Donehower LA, Harvey M, Slagle BL, et al. Mice deficient for p53 are developmentally normal but susceptible to spontaneous tumours. Nature 1992; 356:215.
  53. Lee JM, Abrahamson JL, Kandel R, et al. Susceptibility to radiation-carcinogenesis and accumulation of chromosomal breakage in p53 deficient mice. Oncogene 1994; 9:3731.
  54. Pollock R, Lang A, Ge T, et al. Wild-type p53 and a p53 temperature-sensitive mutant suppress human soft tissue sarcoma by enhancing cell cycle control. Clin Cancer Res 1998; 4:1985.
  55. Ventura A, Kirsch DG, McLaughlin ME, et al. Restoration of p53 function leads to tumour regression in vivo. Nature 2007; 445:661.
  56. Yang CY, Liau JY, Huang WJ, et al. Targeted next-generation sequencing of cancer genes identified frequent TP53 and ATRX mutations in leiomyosarcoma. Am J Transl Res 2015; 7:2072.
  57. Chen X, Bahrami A, Pappo A, et al. Recurrent somatic structural variations contribute to tumorigenesis in pediatric osteosarcoma. Cell Rep 2014; 7:104.
  58. Liau JY, Lee JC, Tsai JH, et al. Comprehensive screening of alternative lengthening of telomeres phenotype and loss of ATRX expression in sarcomas. Mod Pathol 2015; 28:1545.
  59. Flynn RL, Cox KE, Jeitany M, et al. Alternative lengthening of telomeres renders cancer cells hypersensitive to ATR inhibitors. Science 2015; 347:273.
  60. Cance WG, Brennan MF, Dudas ME, et al. Altered expression of the retinoblastoma gene product in human sarcomas. N Engl J Med 1990; 323:1457.
  61. Karpeh MS, Brennan MF, Cance WG, et al. Altered patterns of retinoblastoma gene product expression in adult soft-tissue sarcomas. Br J Cancer 1995; 72:986.
  62. Wunder JS, Czitrom AA, Kandel R, Andrulis IL. Analysis of alterations in the retinoblastoma gene and tumor grade in bone and soft-tissue sarcomas. J Natl Cancer Inst 1991; 83:194.
  63. Oliner JD, Kinzler KW, Meltzer PS, et al. Amplification of a gene encoding a p53-associated protein in human sarcomas. Nature 1992; 358:80.
  64. Flørenes VA, Maelandsmo GM, Forus A, et al. MDM2 gene amplification and transcript levels in human sarcomas: relationship to TP53 gene status. J Natl Cancer Inst 1994; 86:1297.
  65. Khatib ZA, Matsushime H, Valentine M, et al. Coamplification of the CDK4 gene with MDM2 and GLI in human sarcomas. Cancer Res 1993; 53:5535.
  66. Nilbert M, Rydholm A, Willén H, et al. MDM2 gene amplification correlates with ring chromosome in soft tissue tumors. Genes Chromosomes Cancer 1994; 9:261.
  67. Momand J, Zambetti GP, Olson DC, et al. The mdm-2 oncogene product forms a complex with the p53 protein and inhibits p53-mediated transactivation. Cell 1992; 69:1237.
  68. Oliner JD, Pietenpol JA, Thiagalingam S, et al. Oncoprotein MDM2 conceals the activation domain of tumour suppressor p53. Nature 1993; 362:857.
  69. Leach FS, Tokino T, Meltzer P, et al. p53 Mutation and MDM2 amplification in human soft tissue sarcomas. Cancer Res 1993; 53:2231.
  70. Cordon-Cardo C, Latres E, Drobnjak M, et al. Molecular abnormalities of mdm2 and p53 genes in adult soft tissue sarcomas. Cancer Res 1994; 54:794.
  71. Kanoe H, Nakayama T, Murakami H, et al. Amplification of the CDK4 gene in sarcomas: tumor specificity and relationship with the RB gene mutation. Anticancer Res 1998; 18:2317.
  72. Pilotti S, Della Torre G, Lavarino C, et al. Molecular abnormalities in liposarcoma: role of MDM2 and CDK4-containing amplicons at 12q13-22. J Pathol 1998; 185:188.
  73. Aleixo PB, Hartmann AA, Menezes IC, et al. Can MDM2 and CDK4 make the diagnosis of well differentiated/dedifferentiated liposarcoma? An immunohistochemical study on 129 soft tissue tumours. J Clin Pathol 2009; 62:1127.
  74. Llanos S, Efeyan A, Monsech J, et al. A high-throughput loss-of-function screening identifies novel p53 regulators. Cell Cycle 2006; 5:1880.
  75. Narita M, Narita M, Krizhanovsky V, et al. A novel role for high-mobility group a proteins in cellular senescence and heterochromatin formation. Cell 2006; 126:503.
  76. Mayr C, Hemann MT, Bartel DP. Disrupting the pairing between let-7 and Hmga2 enhances oncogenic transformation. Science 2007; 315:1576.
  77. Smith SH, Weiss SW, Jankowski SA, et al. SAS amplification in soft tissue sarcomas. Cancer Res 1992; 52:3746.
  78. Jankowski SA, Mitchell DS, Smith SH, et al. SAS, a gene amplified in human sarcomas, encodes a new member of the transmembrane 4 superfamily of proteins. Oncogene 1994; 9:1205.
  79. Forus A, Flørenes VA, Maelandsmo GM, et al. Mapping of amplification units in the q13-14 region of chromosome 12 in human sarcomas: some amplica do not include MDM2. Cell Growth Differ 1993; 4:1065.
  80. Aiba S, Tabata N, Ishii H, et al. Dermatofibrosarcoma protuberans is a unique fibrohistiocytic tumour expressing CD34. Br J Dermatol 1992; 127:79.
  81. Duda RB, Cundiff D, August CZ, et al. Growth factor receptor and related oncogene determination in mesenchymal tumors. Cancer 1993; 71:3526.
  82. Ladanyl M, Heinemann FS, Huvos AG, et al. Neural differentiation in small round cell tumors of bone and soft tissue with the translocation t(11;22)(q24;q12): an immunohistochemical study of 11 cases. Hum Pathol 1990; 21:1245.
  83. Turc-Carel C, Aurias A, Mugneret F, et al. Chromosomes in Ewing's sarcoma. I. An evaluation of 85 cases of remarkable consistency of t(11;22)(q24;q12). Cancer Genet Cytogenet 1988; 32:229.
  84. Delattre O, Zucman J, Melot T, 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.
  85. Zucman J, Melot T, Desmaze C, et al. Combinatorial generation of variable fusion proteins in the Ewing family of tumours. EMBO J 1993; 12:4481.
  86. Sorensen PH, Lessnick SL, Lopez-Terrada D, et al. A second Ewing's sarcoma translocation, t(21;22), fuses the EWS gene to another ETS-family transcription factor, ERG. Nat Genet 1994; 6:146.
  87. Kawamura-Saito M, Yamazaki Y, Kaneko K, et al. Fusion between CIC and DUX4 up-regulates PEA3 family genes in Ewing-like sarcomas with t(4;19)(q35;q13) translocation. Hum Mol Genet 2006; 15:2125.
  88. Smith SC, Buehler D, Choi EY, et al. CIC-DUX sarcomas demonstrate frequent MYC amplification and ETS-family transcription factor expression. Mod Pathol 2015; 28:57.
  89. Specht K, Sung YS, Zhang L, et al. Distinct transcriptional signature and immunoprofile of CIC-DUX4 fusion-positive round cell tumors compared to EWSR1-rearranged Ewing sarcomas: further evidence toward distinct pathologic entities. Genes Chromosomes Cancer 2014; 53:622.
  90. Sugita S, Arai Y, Tonooka A, et al. A novel CIC-FOXO4 gene fusion in undifferentiated small round cell sarcoma: a genetically distinct variant of Ewing-like sarcoma. Am J Surg Pathol 2014; 38:1571.
  91. Pierron G, Tirode F, Lucchesi C, et al. A new subtype of bone sarcoma defined by BCOR-CCNB3 gene fusion. Nat Genet 2012; 44:461.
  92. Puls F, Niblett A, Marland G, et al. BCOR-CCNB3 (Ewing-like) sarcoma: a clinicopathologic analysis of 10 cases, in comparison with conventional Ewing sarcoma. Am J Surg Pathol 2014; 38:1307.
  93. Boyar RM. Regulation of gonadotropin secretion in man. Med Clin North Am 1978; 62:367.
  94. Cohen-Gogo S, Cellier C, Coindre JM, et al. Ewing-like sarcomas with BCOR-CCNB3 fusion transcript: a clinical, radiological and pathological retrospective study from the Société Française des Cancers de L'Enfant. Pediatr Blood Cancer 2014; 61:2191.
  95. Machado I, Navarro L, Pellin A, et al. Defining Ewing and Ewing-like small round cell tumors (SRCT): The need for molecular techniques in their categorization and differential diagnosis. A study of 200 cases. Ann Diagn Pathol 2016; 22:25.
  96. 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.
  97. 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.
  98. Hisaoka M, Tsuji S, Morimitsu Y, et al. Detection of TLS/FUS-CHOP fusion transcripts in myxoid and round cell liposarcomas by nested reverse transcription-polymerase chain reaction using archival paraffin-embedded tissues. Diagn Mol Pathol 1998; 7:96.
  99. Aman P, Ron D, Mandahl N, et al. Rearrangement of the transcription factor gene CHOP in myxoid liposarcomas with t(12;16)(q13;p11). Genes Chromosomes Cancer 1992; 5:278.
  100. Barone MV, Crozat A, Tabaee A, et al. CHOP (GADD153) and its oncogenic variant, TLS-CHOP, have opposing effects on the induction of G1/S arrest. Genes Dev 1994; 8:453.
  101. dos Santos NR, de Bruijn DR, van Kessel AG. Molecular mechanisms underlying human synovial sarcoma development. Genes Chromosomes Cancer 2001; 30:1.
  102. Clark J, Rocques PJ, Crew AJ, 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; 7:502.
  103. Kawai A, Woodruff J, Healey JH, et al. SYT-SSX gene fusion as a determinant of morphology and prognosis in synovial sarcoma. N Engl J Med 1998; 338:153.
  104. Agus V, Tamborini E, Mezzelani A, et al. Re: A novel fusion gene, SYT-SSX4, in synovial sarcoma. J Natl Cancer Inst 2001; 93:1347.
  105. Kadoch C, Crabtree GR. Reversible disruption of mSWI/SNF (BAF) complexes by the SS18-SSX oncogenic fusion in synovial sarcoma. Cell 2013; 153:71.
  106. Inagaki H, Nagasaka T, Otsuka T, et al. Association of SYT-SSX fusion types with proliferative activity and prognosis in synovial sarcoma. Mod Pathol 2000; 13:482.
  107. Paulino AC. Synovial sarcoma prognostic factors and patterns of failure. Am J Clin Oncol 2004; 27:122.
  108. Mancuso T, Mezzelani A, Riva C, et al. Analysis of SYT-SSX fusion transcripts and bcl-2 expression and phosphorylation status in synovial sarcoma. Lab Invest 2000; 80:805.
  109. Tamborini E, Papini D, Mezzelani A, et al. c-KIT and c-KIT ligand (SCF) in synovial sarcoma (SS): an mRNA expression analysis in 23 cases. Br J Cancer 2001; 85:405.
  110. Barr FG, Nauta LE, Hollows JC. Structural analysis of PAX3 genomic rearrangements in alveolar rhabdomyosarcoma. Cancer Genet Cytogenet 1998; 102:32.
  111. Davis RJ, Barr FG. Fusion genes resulting from alternative chromosomal translocations are overexpressed by gene-specific mechanisms in alveolar rhabdomyosarcoma. Proc Natl Acad Sci U S A 1997; 94:8047.
  112. Ginsberg JP, Davis RJ, Bennicelli JL, et al. Up-regulation of MET but not neural cell adhesion molecule expression by the PAX3-FKHR fusion protein in alveolar rhabdomyosarcoma. Cancer Res 1998; 58:3542.
  113. Linardic CM, Naini S, Herndon JE 2nd, et al. The PAX3-FKHR fusion gene of rhabdomyosarcoma cooperates with loss of p16INK4A to promote bypass of cellular senescence. Cancer Res 2007; 67:6691.
  114. Kelly KM, Womer RB, Sorensen PH, et al. Common and variant gene fusions predict distinct clinical phenotypes in rhabdomyosarcoma. J Clin Oncol 1997; 15:1831.
  115. Kelly KM, Womer RB, Barr FG. Minimal disease detection in patients with alveolar rhabdomyosarcoma using a reverse transcriptase-polymerase chain reaction method. Cancer 1996; 78:1320.
  116. Segal NH, Pavlidis P, Noble WS, et al. Classification of clear-cell sarcoma as a subtype of melanoma by genomic profiling. J Clin Oncol 2003; 21:1775.
  117. Zucman J, Delattre O, Desmaze C, 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.
  118. Coindre JM, Hostein I, Terrier P, 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.
  119. Antonescu CR, Nafa K, Segal NH, et al. 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.
  120. Bu X, Bernstein L. A proposed explanation for female predominance in alveolar soft part sarcoma. Noninactivation of X; autosome translocation fusion gene? Cancer 2005; 103:1245.
  121. Heimann P, Devalck C, Debusscher C, et al. Alveolar soft-part sarcoma: further evidence by FISH for the involvement of chromosome band 17q25. Genes Chromosomes Cancer 1998; 23:194.
  122. Joyama S, Ueda T, Shimizu K, et al. Chromosome rearrangement at 17q25 and xp11.2 in alveolar soft-part sarcoma: A case report and review of the literature. Cancer 1999; 86:1246.
  123. Ladanyi M, Lui MY, Antonescu CR, 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.
  124. Lazar AJ, Das P, Tuvin D, et al. Angiogenesis-promoting gene patterns in alveolar soft part sarcoma. Clin Cancer Res 2007; 13:7314.
  125. Drilon AD, Popat S, Bhuchar G, et al. Extraskeletal myxoid chondrosarcoma: a retrospective review from 2 referral centers emphasizing long-term outcomes with surgery and chemotherapy. Cancer 2008; 113:3364.
  126. Lucas DR, Stenman G. Extraskeletal myxoid chondrosarcoma. In: WHO classification of tumours of soft tissue and bone, 4th, Fletcher CDM, Bridge JA, Hogendoorn PCW, Mertens F (Eds), IARC, Lyon 2013. p.223.
  127. Brody RI, Ueda T, Hamelin A, et al. Molecular analysis of the fusion of EWS to an orphan nuclear receptor gene in extraskeletal myxoid chondrosarcoma. Am J Pathol 1997; 150:1049.
  128. Sandberg AA. Genetics of chondrosarcoma and related tumors. Curr Opin Oncol 2004; 16:342.
  129. Hirabayashi Y, Ishida T, Yoshida MA, et al. Translocation (9;22)(q22;q12). A recurrent chromosome abnormality in extraskeletal myxoid chondrosarcoma. Cancer Genet Cytogenet 1995; 81:33.
  130. Stenman G, Andersson H, Mandahl N, et al. Translocation t(9;22)(q22;q12) is a primary cytogenetic abnormality in extraskeletal myxoid chondrosarcoma. Int J Cancer 1995; 62:398.
  131. Labelle Y, Bussières J, Courjal F, Goldring MB. The EWS/TEC fusion protein encoded by the t(9;22) chromosomal translocation in human chondrosarcomas is a highly potent transcriptional activator. Oncogene 1999; 18:3303.
  132. Filion C, Motoi T, Olshen AB, et al. The EWSR1/NR4A3 fusion protein of extraskeletal myxoid chondrosarcoma activates the PPARG nuclear receptor gene. J Pathol 2009; 217:83.
  133. Hisaoka M, Hashimoto H. Extraskeletal myxoid chondrosarcoma: updated clinicopathological and molecular genetic characteristics. Pathol Int 2005; 55:453.
  134. Filion C, Labelle Y. The oncogenic fusion protein EWS/NOR-1 induces transformation of CFK2 chondrogenic cells. Exp Cell Res 2004; 297:585.
  135. Panagopoulos I, Mertens F, Isaksson M, et al. Molecular genetic characterization of the EWS/CHN and RBP56/CHN fusion genes in extraskeletal myxoid chondrosarcoma. Genes Chromosomes Cancer 2002; 35:340.
  136. Attwooll C, Tariq M, Harris M, et al. Identification of a novel fusion gene involving hTAFII68 and CHN from a t(9;17)(q22;q11.2) translocation in an extraskeletal myxoid chondrosarcoma. Oncogene 1999; 18:7599.
  137. Sjögren H, Wedell B, Meis-Kindblom JM, et al. Fusion of the NH2-terminal domain of the basic helix-loop-helix protein TCF12 to TEC in extraskeletal myxoid chondrosarcoma with translocation t(9;15)(q22;q21). Cancer Res 2000; 60:6832.
  138. Robinson DR, Wu YM, Kalyana-Sundaram S, et al. Identification of recurrent NAB2-STAT6 gene fusions in solitary fibrous tumor by integrative sequencing. Nat Genet 2013; 45:180.
  139. Tanas MR, Sboner A, Oliveira AM, et al. Identification of a disease-defining gene fusion in epithelioid hemangioendothelioma. Sci Transl Med 2011; 3:98ra82.
  140. Patel NR, Salim AA, Sayeed H, et al. Molecular characterization of epithelioid haemangioendotheliomas identifies novel WWTR1-CAMTA1 fusion variants. Histopathology 2015; 67:699.
  141. Doyle LA, Fletcher CD, Hornick JL. Nuclear Expression of CAMTA1 Distinguishes Epithelioid Hemangioendothelioma From Histologic Mimics. Am J Surg Pathol 2016; 40:94.
  142. Antonescu CR, Le Loarer F, Mosquera JM, et al. Novel YAP1-TFE3 fusion defines a distinct subset of epithelioid hemangioendothelioma. Genes Chromosomes Cancer 2013; 52:775.
  143. Chibon F, Lagarde P, Salas S, et al. Validated prediction of clinical outcome in sarcomas and multiple types of cancer on the basis of a gene expression signature related to genome complexity. Nat Med 2010; 16:781.
  144. Barr FG, Chatten J, D'Cruz CM, et al. Molecular assays for chromosomal translocations in the diagnosis of pediatric soft tissue sarcomas. JAMA 1995; 273:553.
  145. Golub TR, Slonim DK, Tamayo P, et al. Molecular classification of cancer: class discovery and class prediction by gene expression monitoring. Science 1999; 286:531.
  146. Nielsen TO, West RB, Linn SC, et al. Molecular characterisation of soft tissue tumours: a gene expression study. Lancet 2002; 359:1301.
  147. Hernando E, Charytonowicz E, Dudas ME, et al. The AKT-mTOR pathway plays a critical role in the development of leiomyosarcomas. Nat Med 2007; 13:748.
  148. Lagarde P, Przybyl J, Brulard C, et al. Chromosome instability accounts for reverse metastatic outcomes of pediatric and adult synovial sarcomas. J Clin Oncol 2013; 31:608.
  149. Sathiakumar N, Delzell E. A review of epidemiologic studies of triazine herbicides and cancer. Crit Rev Toxicol 1997; 27:599.
  150. Dich J, Zahm SH, Hanberg A, Adami HO. Pesticides and cancer. Cancer Causes Control 1997; 8:420.
  151. Lee FI, Smith PM, Bennett B, Williams DM. Occupationally related angiosarcoma of the liver in the United Kingdom 1972-1994. Gut 1996; 39:312.
  152. Lander JJ, Stanley RJ, Sumner HW, et al. Angiosarcoma of the liver associated with Fowler's solution (potassium arsenite). Gastroenterology 1975; 68:1582.
  153. Hardell L, Eriksson M. The association between soft tissue sarcomas and exposure to phenoxyacetic acids. A new case-referent study. Cancer 1988; 62:652.
  154. Wingren G, Fredrikson M, Brage HN, et al. Soft tissue sarcoma and occupational exposures. Cancer 1990; 66:806.
  155. Vineis P, Faggiano F, Tedeschi M, Ciccone G. Incidence rates of lymphomas and soft-tissue sarcomas and environmental measurements of phenoxy herbicides. J Natl Cancer Inst 1991; 83:362.
  156. Kogevinas M, Becher H, Benn T, et al. Cancer mortality in workers exposed to phenoxy herbicides, chlorophenols, and dioxins. An expanded and updated international cohort study. Am J Epidemiol 1997; 145:1061.
  157. Fingerhut MA, Halperin WE, Marlow DA, et al. Cancer mortality in workers exposed to 2,3,7,8-tetrachlorodibenzo-p-dioxin. N Engl J Med 1991; 324:212.
  158. The association of selected cancers with service in the US military in Vietnam. II. Soft-tissue and other sarcomas. The Selected Cancers Cooperative Study Group. Arch Intern Med 1990; 150:2485.
  159. Hoppin JA, Tolbert PE, Herrick RF, et al. Occupational chlorophenol exposure and soft tissue sarcoma risk among men aged 30-60 years. Am J Epidemiol 1998; 148:693.
  160. Stewart FW, Treves N. Classics in oncology: lymphangiosarcoma in postmastectomy lymphedema: a report of six cases in elephantiasis chirurgica. CA Cancer J Clin 1981; 31:284.
  161. Tomita K, Yokogawa A, Oda Y, Terahata S. Lymphangiosarcoma in postmastectomy lymphedema (Stewart-Treves syndrome): ultrastructural and immunohistologic characteristics. J Surg Oncol 1988; 38:275.
  162. Muller R, Hajdu SI, Brennan MF. Lymphangiosarcoma associated with chronic filarial lymphedema. Cancer 1987; 59:179.
  163. Sieweke MH, Thompson NL, Sporn MB, Bissell MJ. Mediation of wound-related Rous sarcoma virus tumorigenesis by TGF-beta. Science 1990; 248:1656.
  164. Martins-Green M, Boudreau N, Bissell MJ. Inflammation is responsible for the development of wound-induced tumors in chickens infected with Rous sarcoma virus. Cancer Res 1994; 54:4334.
  165. Purgina B, Rao UN, Miettinen M, Pantanowitz L. AIDS-Related EBV-Associated Smooth Muscle Tumors: A Review of 64 Published Cases. Patholog Res Int 2011; 2011:561548.
  166. Cheuk W, Li PC, Chan JK. Epstein-Barr virus-associated smooth muscle tumour: a distinctive mesenchymal tumour of immunocompromised individuals. Pathology 2002; 34:245.
  167. Lee ES, Locker J, Nalesnik M, et al. The association of Epstein-Barr virus with smooth-muscle tumors occurring after organ transplantation. N Engl J Med 1995; 332:19.
  168. McClain KL, Leach CT, Jenson HB, et al. Association of Epstein-Barr virus with leiomyosarcomas in young people with AIDS. N Engl J Med 1995; 332:12.