Skip to main content
SpringerLink
Log in
Book cover

Cañadell's Pediatric Bone Sarcomas pp 57–73Cite as

Molecular Biology of Pediatric Bone Sarcomas

  • Chapter
  • First Online:

  • 577 Accesses

Abstract

Genetic studies can help in the diagnosis and treatment of pediatric bone sarcoma patients as well as in the determination of prognosis for these patients. New drugs and targeted therapies are currently under development as a result of recent advances in molecular biology.

This is a preview of subscription content, log in via an institution.

Chapter
USD   29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD   84.99
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD   159.00
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD   109.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Learn about institutional subscriptions

References

  1. Clark JC, Dass CR, Choong PF. A review of clinical and molecular prognostic factors in osteosarcoma. J Cancer Res Clin Oncol. 2008;134:281–97.

    Article  CAS  PubMed  Google Scholar 

  2. Martin JM, Squire JA, Zielenska M. The genetics of osteosarcoma. Sarcoma. 2012;2012:627254.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  3. Soussi T, Leblanc T, Baruchel A, Schaison G. Germline mutations of the p53 tumor-suppressor gene in cancer-prone families: a review. Nouv Rev Fr Hematol. 1993;35:33–6.

    CAS  PubMed  Google Scholar 

  4. Mirabello L, Yeager M, Mai PL, Gastier-Foster JM, Gorlick R, Khanna C, Patiño-Garcia A, Sierrasesúmaga L, Lecanda F, Andrulis IL, Wunder JS, Gokgoz N, Barkauskas DA, Zhang X, Vogt A, Jones K, Boland JF, Chanock SJ, Savage SA. Germline TP53 variants and susceptibility to osteosarcoma. J Natl Cancer Inst. 2015;107(7):djv101.

    Google Scholar 

  5. Kaseta MK, Khaldi L, Gomatos IP, et al. Prognostic value of bax, bcl-2, and p53 staining in primary osteosarcoma. J Surg Oncol. 2008;97:259–66.

    Article  PubMed  Google Scholar 

  6. Wunder JS, Gokgoz N, Parkes R, et al. TP53 mutations and outcome in osteosarcoma: a prospective, multicenter study. J Clin Oncol. 2005;23:1483–90.

    Article  CAS  PubMed  Google Scholar 

  7. Belchis DA, Gocke CD, Geradts J. Alterations in the rb, p16, and cyclin d1 cell cycle control pathway in osteosarcomas. Pediatr Pathol Mol Med. 2000;19:377–89.

    Article  CAS  Google Scholar 

  8. Yamaguchi T, Toguchida J, Yamamuro T, et al. Allelotype analysis in osteosarcomas: frequent allele loss on 3q, 13q, 17p, and 18q. Cancer Res. 1992;52:2419–23.

    CAS  PubMed  Google Scholar 

  9. Wadayama B, Feugeas O, Guriec N, et al. Loss of heterozygosity of the RB gene is a poor prognostic factor in patients with osteosarcoma. J Clin Oncol. 1996;14:467–72.

    Article  Google Scholar 

  10. Benassi MS, Molendini L, Gamberi G, et al. Alteration of pRb/p16/cdk4 regulation in human osteosarcoma. Int J Cancer. 1999;84:489–93.

    Article  CAS  PubMed  Google Scholar 

  11. Wadayama B, Toguchida J, Shimizu T, et al. Mutation spectrum of the retinoblastoma gene in osteosarcomas. Cancer Res. 1994;54:3042–8.

    CAS  PubMed  Google Scholar 

  12. Patiño-García A, Piñeiro ES, Díez MZ, Iturriagagoitia LG, Klüssmann FA, Ariznabarreta LS. Genetic and epigenetic alterations of the cell cycle regulators and tumor suppressor genes in pediatric osteosarcomas. J Pediatr Hematol Oncol. 2003;25:362–7.

    Article  PubMed  Google Scholar 

  13. 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;83:194–200.

    Article  CAS  PubMed  Google Scholar 

  14. Heinsohn S, Evermann U, Zur Stadt U, Bielack S, Kabisch H. Determination of the prognostic value of loss of heterozygosity at the retinoblastoma gene in osteosarcoma. Int J Oncol. 2007;30:1205–14.

    CAS  PubMed  Google Scholar 

  15. Chen K, Fallen S, Abaan HO, Hayran M, et al. WNT10b induces chemotaxis of osteosarcoma and correlates with reduced survival. Pediatr Blood Cancer. 2008;51:349–55.

    Article  CAS  PubMed  Google Scholar 

  16. Hoang BH, Kubo T, Healey JH, et al. Expression of LDL receptor-related protein 5 (LRP5) as a novel marker for disease progression in high-grade osteosarcoma. Int J Cancer. 2004;109:106–11.

    Article  CAS  PubMed  Google Scholar 

  17. Gill J, Geller D, Gorlick R. HER-2 involvement in osteosarcoma. Adv Exp Med Biol. 2014;804:161–77.

    Article  CAS  PubMed  Google Scholar 

  18. Ebb D, Meyers P, Grier H, Bernstein M, Gorlick R, Lipshultz SE, Krailo M, Devidas M, Barkauskas DA, Siegal GP, Ferguson WS, Letson GD, Marcus K, Goorin A, Beardsley P, Marina N. Phase II trial of trastuzumab in combination with cytotoxic chemotherapy for treatment of metastatic osteosarcoma with human epidermal growth factor receptor 2 overexpression: a report from the children’s oncology group. J Clin Oncol. 2012;30:2545–51.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Ren L, Khanna C. Role of ezrin in osteosarcoma metastasis. Adv Exp Med Biol. 2014;804:181–201.

    Article  CAS  PubMed  Google Scholar 

  20. Chavez Kappel C, Velez-Yanguas C, Hirschfeld S, Helman LJ. Human osteosarcoma cell lines are dependent on insulin-like growth factor for in vitro growth. Cancer Res. 1994;54:2803–7.

    Google Scholar 

  21. Rodriguez-Galindo C, Poquette CA, Daw NC, Tan M, Meyer WH, Cleveland JL. Circulating concentrations of IGF-I and IGFBP-3 are not predictive of incidence or clinical behavior of pediatric osteosarcoma. Med Pediatr Oncol. 2001;36:605–11.

    Article  CAS  PubMed  Google Scholar 

  22. Ek ET, Ojaimi J, Kitagawa Y, Choong PF. Does the degree of intratumoral microvessel density and VEGF expression have prognostic significance in osteosarcoma. Oncol Rep. 2006;16:17–23.

    CAS  PubMed  Google Scholar 

  23. Kreuter M, Bieker R, Bielack SS, et al. Prognostic relevance of increased angiogenesis in osteosarcoma. Clin Cancer Res. 2004;10:8531–7.

    Article  PubMed  Google Scholar 

  24. Stempak D, Gammon J, Halton J, Moghrabi A, Koren G, Baruchel S. A pilot pharmacokinetic and antiangiogenic biomarker study of celecoxib and low-dose metronomic vinblastine or cyclophosphamide in pediatric recurrent solid tumors. J Pediatr Hematol Oncol. 2006;28:720–8.

    Article  CAS  PubMed  Google Scholar 

  25. Foukas AF, Deshmukh NS, Grimer RJ, Mangham DC, Mangos EG, Taylor S. Stage-IIB osteosarcomas around the knee A study of MMP-9 in surviving tumor cells. J Bone Joint Surg Br. 2002;84:706–11.

    Article  CAS  PubMed  Google Scholar 

  26. Kido A, Tsutsumi M, Iki K, et al. Overexpression of matrix metalloproteinase (MMP)-9 correlates with metastatic potency of spontaneous and 4-hydroxyaminoquinoline 1-oxide (4-HAQO)-induced transplantable osteosarcomas in rats. Cancer Lett. 1999;137:209–16.

    Article  CAS  PubMed  Google Scholar 

  27. Pakos EE, Ioannidis JP. The association of P-glycoprotein with response to chemotherapy and clinical outcome in patients with osteosarcoma A meta-analysis. Cancer. 2003;98(3):581–9.

    Article  CAS  PubMed  Google Scholar 

  28. Baldini N, Scotlandi K, Serra M, et al. P-glycoprotein expression in osteosarcoma: a basis for risk-adapted adjuvant chemotherapy. J Orthop Res. 1999;17:629–32.

    Article  CAS  PubMed  Google Scholar 

  29. Park YB, Kim HS, Oh JH, Lee SH. The co-expression of p53 protein and P-glycoprotein is correlated to a poor prognosis in osteosarcoma. Int Orthop. 2001;24:307–10.

    Article  CAS  PubMed  Google Scholar 

  30. Sandberg AA, Bridge JA. Updates on the cytogenetics and molecular genetics of bone and soft tissue tumors: osteosarcoma and related tumors. Cancer Genet Cytogenet. 2003;145:1–30. 32.

    Article  CAS  PubMed  Google Scholar 

  31. Squire JA, Pei J, Marrano P, et al. High-resolution mapping of amplifi cations and deletions in pediatric osteosarcoma by use of CGH analysis of cDNA microarrays. Genes Chromosomes Cancer. 2003;38:215–25.

    Article  CAS  PubMed  Google Scholar 

  32. Forus A, Weghuis DO, Smeets D, Fodstad O, Myklebost O, Geurts van Kessel A. Comparative genomic hybridization analysis of human sarcomas: II. Identification of novel amplicons at 6p and 17p in osteosarcomas. Genes Chromosomes Cancer. 1995;14:15–21.

    Article  CAS  PubMed  Google Scholar 

  33. Tarkkanen M, Karhu R, Kallioniemi A, et al. Gains and losses of DNA sequences in osteosarcomas by comparative genomic hybridization. Cancer Res. 1995;55:1334–8.

    CAS  PubMed  Google Scholar 

  34. Zielenska M, Marrano P, Thorner P, et al. High-resolution cDNA microarray CGH mapping of genomic imbalances in osteosarcoma using formalin-fi xed paraffi n-embedded tissue. Cytogenet Genome Res. 2004;107:77–82.

    Article  CAS  PubMed  Google Scholar 

  35. Ozaki T, Schaefer KL, Wai D, et al. Genetic imbalances revealed by comparative genomic hybridization in osteosarcomas. Int J Cancer. 2002;102:355–65.

    Article  CAS  PubMed  Google Scholar 

  36. Savage SA, Mirabello L, Wang Z, Gastier-Foster JM, Gorlick R, Khanna C, Flanagan AM, Tirabosco R, Andrulis IL, Wunder JS, Gokgoz N, Patiño-Garcia A, Sierrasesúmaga L, Lecanda F, Kurucu N, Ilhan IE, Sari N, Serra M, Hattinger C, Picci P, Spector LG, Barkauskas DA, Marina N, de Toledo SR, Petrilli AS, Amary MF, Halai D, Thomas DM, Douglass C, Meltzer PS, Jacobs K, Chung CC, Berndt SI, Purdue MP, Caporaso NE, Tucker M, Rothman N, Landi MT, Silverman DT, Kraft P, Hunter DJ, Malats N, Kogevinas M, Wacholder S, Troisi R, Helman L, Fraumeni Jr JF, Yeager M, Hoover RN, Chanock SJ. Genome-wide association study identifies two susceptibility loci for osteosarcoma. Nat Genet. 2013;45:799–803.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Gurney JG, Davis S, Severson RK, Fang JY, Ross JA, Robison LL. Trends in cancer incidence among children in the U.S. Cancer. 1996;78:532–41.

    Article  CAS  PubMed  Google Scholar 

  38. Arndt CA, Crist WM. Common musculoskeletal tumors of childhood and adolescence. N Engl J Med. 1999;341:342–52.

    Article  CAS  PubMed  Google Scholar 

  39. de Alava E, Gerald WL. Molecular biology of the Ewing’s sarcoma/primitive neuroectodermal tumor family. J Clin Oncol. 2000;18:204–13.

    Article  PubMed  Google Scholar 

  40. Grier HE. The Ewing family of tumors Ewing’s sarcoma and primitive neuroectodermal tumors. Pediatr Clin North Am. 1997;44:991–1004.

    Article  CAS  PubMed  Google Scholar 

  41. Franchi A, Pasquinelli G, Cenacchi G, et al. Immunohistochemical and ultrastructural investigation of neural differentiation in Ewing sarcoma/PNET of bone and soft tissues. Ultrastruct Pathol. 2001;25:219–25.

    Article  CAS  PubMed  Google Scholar 

  42. Kovar H, Dworzak M, Strehl S, et al. Overexpression of the pseudoautosomal gene MIC2 in Ewing’s sarcoma and peripheral primitive neuroectodermal tumor. Oncogene. 1990;5:1067–70.

    CAS  PubMed  Google Scholar 

  43. Ushigome SMR, Sorensen PH. Ewing sarcoma/Primitive Neuroectodermal Tumor (PNET). In: Christopher DM, Fletcher KKU, Fredrik M, editors. Pathology and genetics of tumors of soft tissue and Bone World Health Organization classification of tumors. Lyon: Pathology and Genetics of Tumors of Soft Tissue and Bone International Agency for Research on Cancer; 2002.

    Google Scholar 

  44. Peter M, Gilbert E, Delattre O. A multiplex real-time PCR assay for the detection of gene fusions observed in solid tumors. Lab Invest. 2001;81:905–12.

    Article  CAS  PubMed  Google Scholar 

  45. Burchill SA. Ewing’s sarcoma: diagnostic, prognostic, and therapeutic implications of molecular abnormalities. J Clin Pathol. 2003;56:96–102.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Paulussen M, Ahrens S, Craft AW, et al. Ewing’s tumors with primary lung metastases: survival analysis of 114 (European Intergroup) Cooperative Ewing’s Sarcoma Studies patients. J Clin Oncol. 1998;16:3044–52.

    Article  CAS  PubMed  Google Scholar 

  47. Cotterill SJ, Ahrens S, Paulussen M, et al. Prognostic factors in Ewing’s tumor of bone: analysis of 975 patients from the European Intergroup Cooperative Ewing’s Sarcoma Study Group. J Clin Oncol. 2000;18:3108–14.

    Article  CAS  PubMed  Google Scholar 

  48. Mackall CL, Meltzer PS, Helman LJ. Focus on sarcomas. Cancer Cell. 2002;2:175–8.

    Article  CAS  PubMed  Google Scholar 

  49. Delattre O, Zucman J, Plougastel B, et al. Gene fusion with an ETS DNA-binding domain caused by chromosome translocation in human tumors. Nature. 1992;359:162–5.

    Article  CAS  PubMed  Google Scholar 

  50. de Alava E, Kawai A, Healey JH, et al. EWS-FLI1 fusion transcript structure is an independent determinant of prognosis in Ewing’s sarcoma. J Clin Oncol. 1998;16:1248–55.

    Article  PubMed  Google Scholar 

  51. Zoubek A, Dockhorn-Dworniczak B, Delattre O, et al. Does expression of different EWS chimeric transcripts define clinically distinct risk groups of Ewing tumor patients. J Clin Oncol. 1996;14:1245–51.

    Article  CAS  PubMed  Google Scholar 

  52. Ben-David Y, Giddens EB, Letwin K, Bernstein A. Erythroleukemia induction by Friend murine leukemia virus: insertional activation of a new member of the ets gene family, Fli-1, closely linked to c-ets-1. Genes Dev. 1991;5:908–18.

    Article  CAS  PubMed  Google Scholar 

  53. Melet F, Motro B, Rossi DJ, Zhang L, Bernstein A. Generation of a novel Fli-1 protein by gene targeting leads to a defect in thymus development and a delay in friend virus-induced erythroleukemia. Mol Cell Biol. 1996;16:2708–18.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Ohno T, Ouchida M, Lee L, Gatalica Z, Rao VN, Reddy ES. The EWS gene, involved in Ewing family of tumors, malignant melanoma of soft parts and desmoplastic small round cell tumors, codes for an RNA binding protein with novel regulatory domains. Oncogene. 1994;9:3087–97.

    CAS  PubMed  Google Scholar 

  55. Bertolotti A, Lutz Y, Heard DJ, Chambon P, Tora L. hTAF(II)68, a novel RNA/ssDNA-binding protein with homology to the pro-oncoproteins TLS/FUS and EWS is associated with both TFIID and RNA polymerase II. EMBO J. 1996;15:5022–31.

    CAS  PubMed  PubMed Central  Google Scholar 

  56. Aman P, Panagopoulos I, Lassen C, et al. Expression patterns of the human sarcoma-associated genes FUS and EWS and the genomic structure of FUS. Genomics. 1996;37:1–8.

    Article  CAS  PubMed  Google Scholar 

  57. Shing DC, McMullan DJ, Roberts P, et al. FUS/ERG gene fusions in Ewing’s tumors. Cancer Res. 2003;63:4568–76.

    CAS  PubMed  Google Scholar 

  58. Crozat A, Aman P, Mandahl N, Ron D. Fusion of CHOP to a novel RNA-binding protein in human myxoid liposarcoma. Nature. 1993;363:640–4.

    Article  CAS  PubMed  Google Scholar 

  59. Labelle Y, Zucman J, Stenman G, et al. Oncogenic conversion of a novel orphan nuclear receptor by chromosome translocation. Hum Mol Genet. 1995;4:2219–26.

    Article  CAS  PubMed  Google Scholar 

  60. Ladanyi M, Gerald W. Fusion of the EWS and WT1 genes in the desmoplastic small round cell tumor. Cancer Res. 1994;54:2837–40.

    CAS  PubMed  Google Scholar 

  61. Petermann R, Mossier BM, Aryee DN, Khazak V, Golemis EA, Kovar H. Oncogenic EWS-Fli1 interacts with hsRPB7, a subunit of human RNA polymerase II. Oncogene. 1998;17:603–10.

    Article  CAS  PubMed  Google Scholar 

  62. Yang L, Chansky HA, Hickstein DD. EWS. Fli-1 fusion protein interacts with hyperphosphorylated RNA polymerase II and interferes with serine-arginine protein-mediated RNA splicing. J Biol Chem. 2000;275:37612–8.

    Article  CAS  PubMed  Google Scholar 

  63. Knoop LL, Baker SJ. The splicing factor U1C represses EWS/FLI-mediated transactivation. J Biol Chem. 2000;275:24865–71.

    Article  CAS  PubMed  Google Scholar 

  64. Knoop LL, Baker SJ. EWS/FLI alters 5′ ¢ -splice site selection. J Biol Chem. 2001;276:22317–22.

    Article  CAS  PubMed  Google Scholar 

  65. Spahn L, Petermann R, Siligan C, Schmid JA, Aryee DN, Kovar H. Interaction of the EWS NH2 terminus with BARD1 links the Ewing’s sarcoma gene to a common tumor suppressor pathway. Cancer Res. 2002;62:4583–7.

    CAS  PubMed  Google Scholar 

  66. May WA, Gishizky ML, Lessnick SL, et al. Ewing sarcoma 11;22 translocation produces a chimeric transcription factor that requires the DNA-binding domain encoded by FLI1 for transformation. Proc Natl Acad Sci USA. 1993;90:5752–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Lessnick SL, Braun BS, Denny CT, May WA. Multiple domains mediate transformation by the Ewing’s sarcoma EWS/FLI-1 fusion gene. Oncogene. 1995;10:423–31.

    CAS  PubMed  Google Scholar 

  68. Janknecht R, Nordheim A. Gene regulation by Ets proteins. Biochim Biophys Acta. 1993;1155:346–56.

    CAS  PubMed  Google Scholar 

  69. Huang HY, Illei PB, Zhao Z, et al. Ewing sarcomas with p53 mutation or p16/p14ARF homozygous deletion: a highly lethal subset associated with poor chemoresponse. J Clin Oncol. 2005;23:548–58.

    Article  CAS  PubMed  Google Scholar 

  70. Zucman J, Melot T, Desmaze C, et al. Combinatorial generation of variable fusion proteins in the Ewing family of tumors. EMBO J. 1993;12:4481–7.

    CAS  PubMed  PubMed Central  Google Scholar 

  71. Jeon IS, Davis JN, Braun BS, et al. A variant Ewing’s sarcoma translocation (7;22) fuses the EWS gene to the ETS gene ETV1. Oncogene. 1995;10:1229–34.

    CAS  PubMed  Google Scholar 

  72. Kaneko Y, Yoshida K, Handa M, et al. Fusion of an ETS-family gene, EIAF, to EWS by t(17;22)(q12;q12) chromosome translocation in an undifferentiated sarcoma of infancy. Genes Chromosomes Cancer. 1996;15:115–21.

    Article  CAS  PubMed  Google Scholar 

  73. Peter M, Couturier J, Pacquement H, et al. A new member of the ETS family fused to EWS in Ewing tumors. Oncogene. 1997;14:1159–64.

    Article  CAS  PubMed  Google Scholar 

  74. Torchia EC, Jaishankar S, Baker SJ. Ewing tumor fusion proteins block the differentiation of pluripotent marrow stromal cells. Cancer Res. 2003;63:3464–8.

    CAS  PubMed  Google Scholar 

  75. Gonzalez I, Vicent S, de Alava E, Lecanda F. EWS/FLI-1 oncoprotein subtypes impose different requirements for transformation and metastatic activity in a murine model. J Mol Med. 2007;85:1015–29.

    Article  CAS  PubMed  Google Scholar 

  76. Gershon TR, Oppenheimer O, Chin SS, Gerald WL. Temporally regulated neural crest transcription factors distinguish neuroectodermal tumors of varying malignancy and differentiation. Neoplasia. 2005;7:575–84.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Teitell MA, Thompson AD, Sorensen PH, Shimada H, Triche TJ, Denny CT. EWS/ETS fusion genes induce epithelial and neuroectodermal differentiation in NIH 3 T3 fibroblasts. Lab Invest. 1999;79:1535–43.

    CAS  PubMed  Google Scholar 

  78. Rorie CJ, Thomas VD, Chen P, Pierce HH, O’Bryan JP, Weissman BE. The Ews/Fli-1 fusion gene switches the differentiation program of neuroblastomas to Ewing sarcoma/peripheral primitive neuroectodermal tumors. Cancer Res. 2004;64:1266–77.

    Article  CAS  PubMed  Google Scholar 

  79. Hu-Lieskovan S, Zhang J, Wu L, Shimada H, Schofield DE, Triche TJ. EWS-FLI1 fusion protein up-regulates critical genes in neural crest development and is responsible for the observed phenotype of Ewing’s family of tumors. Cancer Res. 2005;65:4633–44.

    Article  CAS  PubMed  Google Scholar 

  80. Deneen B, Denny CT. Loss of p16 pathways stabilizes EWS/FLI1 expression and complements EWS/FLI1 mediated transformation. Oncogene. 2001;20:6731–41.

    Article  CAS  PubMed  Google Scholar 

  81. Castillero-Trejo Y, Eliazer S, Xiang L, Richardson JA, Ilaria Jr RL. Expression of the EWS/FLI-1 oncogene in murine primary bone-derived cells results in EWS/FLI-1-dependent, Ewing sarcoma-like tumors. Cancer Res. 2005;65:8698–705.

    Article  CAS  PubMed  Google Scholar 

  82. Riggi N, Cironi L, Provero P, et al. Development of Ewing’s sarcoma from primary bone marrow-derived mesenchymal progenitor cells. Cancer Res. 2005;65:11459–68.

    Article  CAS  PubMed  Google Scholar 

  83. Tolar J, Nauta AJ, Osborn MJ, et al. Sarcoma derived from cultured mesenchymal stem cells. Stem Cells. 2007;25:371–9.

    Article  CAS  PubMed  Google Scholar 

  84. Rangarajan A, Hong SJ, Gifford A, Weinberg RA. Species- and cell type-specific requirements for cellular transformation. Cancer Cell. 2004;6:171–83.

    Article  CAS  PubMed  Google Scholar 

  85. Riggi N, Suva ML, Suva D, et al. EWS-FLI-1 expression triggers a Ewing’s sarcoma initiation program in primary human mesenchymal stem cells. Cancer Res. 2008;68:2176–85.

    Article  CAS  PubMed  Google Scholar 

  86. Tirode F, Laud-Duval K, Prieur A, Delorme B, Charbord P, Delattre O. Mesenchymal stem cell features of Ewing tumors. Cancer Cell. 2007;11:421–9.

    Article  CAS  PubMed  Google Scholar 

  87. Szuhai K, Ijszenga M, Tanke HJ, Rosenberg C, Hogendoorn PC. Molecular cytogenetic characterization of four previously established and two newly established Ewing sarcoma cell lines. Cancer Genet Cytogenet. 2006;166:173–9.

    Article  CAS  PubMed  Google Scholar 

  88. Kovar H, Jug G, Aryee DN, et al. Among genes involved in the RB dependent cell cycle regulatory cascade, the p16 tumor suppressor gene is frequently lost in the Ewing family of tumors. Oncogene. 1997;15:2225–32.

    Article  CAS  PubMed  Google Scholar 

  89. Tsuchiya T, Sekine K, Hinohara S, Namiki T, Nobori T, Kaneko Y. Analysis of the p16INK4, p14ARF, p15, TP53, and MDM2 genes and their prognostic implications in osteosarcoma and Ewing sarcoma. Cancer Genet Cytogenet. 2000;120:91–8.

    Article  CAS  PubMed  Google Scholar 

  90. Lopez-Guerrero JA, Pellin A, Noguera R, Carda C, Llombart-Bosch A. Molecular analysis of the 9p21 locus and p53 genes in Ewing family tumors. Lab Invest. 2001;81:803–14.

    Article  CAS  PubMed  Google Scholar 

  91. Bonnet D, Dick JE. Human acute myeloid leukemia is organized as a hierarchy that originates from a primitive hematopoietic cell. Nat Med. 1997;3:730–7.

    Article  CAS  PubMed  Google Scholar 

  92. Jamieson CH, Weissman IL, Passegue E. Chronic versus acute myelogenous leukemia: a question of self-renewal. Cancer Cell. 2004;6:531–3.

    CAS  PubMed  Google Scholar 

  93. Smith R, Owen LA, Trem DJ, et al. Expression profiling of EWS/FLI identifies NKX2.2 as a critical target gene in Ewing’s sarcoma. Cancer Cell. 2006;9:405–16.

    Article  CAS  PubMed  Google Scholar 

  94. Owen LA, Kowalewski AA, Lessnick SL. EWS/FLI mediates transcriptional repression via NKX2.2 during oncogenic transformation in Ewing’s sarcoma. PLoS One. 2008;3:e1965.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  95. Fukuma M, Okita H, Hata J, Umezawa A. Upregulation of Id2, an oncogenic helix-loophelix protein, is mediated by the chimeric EWS/ets protein in Ewing sarcoma. Oncogene. 2003;22:1–9.

    Article  CAS  PubMed  Google Scholar 

  96. Nishimori H, Sasaki Y, Yoshida K, et al. The Id2 gene is a novel target of transcriptional activation by EWS-ETS fusion proteins in Ewing family tumors. Oncogene. 2002;21:8302–9.

    Article  CAS  PubMed  Google Scholar 

  97. Zwerner JP, May WA. PDGF-C is an EWS/FLI induced transforming growth factor in Ewing family tumors. Oncogene. 2001;20:626–33.

    Article  CAS  PubMed  Google Scholar 

  98. Matsumoto Y, Tanaka K, Nakatani F, Matsunobu T, Matsuda S, Iwamoto Y. Downregulation and forced expression of EWS-Fli1 fusion gene results in changes in the expression of G(1) regulatory genes. Br J Cancer. 2001;84:768–75.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Wai DH, Schaefer KL, Schramm A, et al. Expression analysis of pediatric solid tumor cell lines using oligonucleotide microarrays. Int J Oncol. 2002;20:441–51.

    CAS  PubMed  Google Scholar 

  100. Dauphinot L, De Oliveira C, Melot T, et al. Analysis of the expression of cell cycle regulators in Ewing cell lines: EWS-FLI-1 modulates p57KIP2and c-Myc expression. Oncogene. 2001;20:3258–65.

    Article  CAS  PubMed  Google Scholar 

  101. Bailly RA, Bosselut R, Zucman J, et al. DNA-binding and transcriptional activation properties of the EWS-FLI-1 fusion protein resulting from the t(11;22) translocation in Ewing sarcoma. Mol Cell Biol. 1994;14:3230–41.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Takahashi A, Higashino F, Aoyagi M, et al. EWS/ETS fusions activate telomerase in Ewing’s tumors. Cancer Res. 2003;63:8338–44.

    CAS  PubMed  Google Scholar 

  103. Nakatani F, Tanaka K, Sakimura R, et al. Identification of p21WAF1/CIP1 as a direct target of EWS-Fli1 oncogenic fusion protein. J Biol Chem. 2003;278:15105–15.

    Article  CAS  PubMed  Google Scholar 

  104. Hahm KB. Repression of the gene encoding the TGF-beta type II receptor is a major target of the EWS-FLI1 oncoprotein. Nat Genet. 1999;23:481.

    Article  PubMed  CAS  Google Scholar 

  105. Im YH, Kim HT, Lee C, et al. EWS-FLI1, EWS-ERG, and EWS-ETV1 oncoproteins of Ewing tumor family all suppress transcription of transforming growth factor beta type II receptor gene. Cancer Res. 2000;60:1536–40.

    CAS  PubMed  Google Scholar 

  106. Prieur A, Tirode F, Cohen P, Delattre O. EWS/FLI-1 silencing and gene profiling of Ewing cells reveal downstream oncogenic pathways and a crucial role for repression of insulin-like growth factor binding protein 3. Mol Cell Biol. 2004;24:7275–83.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Scotlandi K, Benini S, Nanni P, et al. Blockage of insulin-like growth factor-I receptor inhibits the growth of Ewing’s sarcoma in athymic mice. Cancer Res. 1998;58:4127–31.

    CAS  PubMed  Google Scholar 

  108. Scotlandi K, Avnet S, Benini S, et al. Expression of an IGF-I receptor dominant negative mutant induces apoptosis, inhibits tumorigenesis and enhances chemosensitivity in Ewing’s sarcoma cells. Int J Cancer. 2002;101:11–6.

    Article  CAS  PubMed  Google Scholar 

  109. Scotlandi K, Maini C, Manara MC, et al. Effectiveness of insulin-like growth factor I receptor antisense strategy against Ewing’s sarcoma cells. Cancer Gene Ther. 2002;9:296–307.

    Article  CAS  PubMed  Google Scholar 

  110. Manara MC, Landuzzi L, Nanni P, et al. Preclinical in vivo study of new insulin-like growth factor-I receptor-specific inhibitor in Ewing’s sarcoma. Clin Cancer Res. 2007;13:1322–30.

    Article  CAS  PubMed  Google Scholar 

  111. Kinsey M, Smith R, Lessnick SL. NR0B1 is required for the oncogenic phenotype mediated by EWS/FLI in Ewing’s sarcoma. Mol Cancer Res. 2006;4:851–9.

    Article  CAS  PubMed  Google Scholar 

  112. Garcia-Aragoncillo E, Carrillo J, Lalli E, et al. DAX1, a direct target of EWS/FLI1 oncoprotein, is a principal regulator of cell-cycle progression in Ewing’s tumor cells. Oncogene. 2008.

    Google Scholar 

  113. Mendiola M, Carrillo J, Garcia E, et al. The orphan nuclear receptor DAX1 is up-regulated by the EWS/FLI1 oncoprotein and is highly expressed in Ewing tumors. Int J Cancer. 2006;118:1381–9.

    Article  CAS  PubMed  Google Scholar 

  114. Selvanathan SP, Graham GT, Erkizan HV, Dirksen U, Natarajan TG, Dakic A, Yu S, Liu X, Paulsen MT, Ljungman ME, Wu CH, Lawlor ER, Üren A, Toretsky JA. Oncogenic fusion protein EWS-FLI1 is a network hub that regulates alternative splicing. Proc Natl Acad Sci USA. 2015;112:E1307–16.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Marques Howarth M, Simpson D, Ngok SP, Nieves B, Chen R, Siprashvili Z, Vaka D, Breese MR, Crompton BD, Alexe G, Hawkins DS, Jacobson D, Brunner AL, West R, Mora J, Stegmaier K, Khavari P, Sweet-Cordero EA. Long noncoding RNA EWSAT1-mediated gene repression facilitates Ewing sarcoma oncogenesis. J Clin Invest. 2014;124:5275–90.

    Article  PubMed  PubMed Central  Google Scholar 

  116. Brohl AS, Solomon DA, Chang W, Wang J, Song Y, Sindiri S, Patidar R, Hurd L, Chen L, Shern JF, Liao H, Wen X, Gerard J, Kim JS, Lopez Guerrero JA, Machado I, Wai DH, Picci P, Triche T, Horvai AE, Miettinen M, Wei JS, Catchpool D, Llombart-Bosch A, Waldman T, Khan J. The genomic landscape of the Ewing Sarcoma family of tumors reveals recurrent STAG2 mutation. PLoS Genet. 2014;10:e1004475.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  117. Tirode F, Surdez D, Ma X, Parker M, Le Deley MC, Bahrami A, Zhang Z, Lapouble E, Grossetête-Lalami S, Rusch M, Reynaud S, Rio-Frio T, Hedlund E, Wu G, Chen X, Pierron G, Oberlin O, Zaidi S, Lemmon G, Gupta P, Vadodaria B, Easton J, Gut M, Ding L, Mardis ER, Wilson RK, Shurtleff S, Laurence V, Michon J, Marec-Bérard P, Gut I, Downing J, Dyer M, Zhang J, Delattre O, Jude Children’s Research Hospital–Washington University Pediatric Cancer Genome Project and the International Cancer Genome Consortium. Genomic landscape of Ewing sarcoma defines an aggressive subtype with co-association of STAG2 and TP53 mutations. Cancer Discov. 2014;4:1342–53.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Riggi N, Knoechel B, Gillespie SM, Rheinbay E, Boulay G, Suvà ML, Rossetti NE, Boonseng WE, Oksuz O, Cook EB, Formey A, Patel A, Gymrek M, Thapar V, Deshpande V, Ting DT, Hornicek FJ, Nielsen GP, Stamenkovic I, Aryee MJ, Bernstein BE, Rivera MN. EWS-FLI1 utilizes divergent chromatin remodeling mechanisms to directly activate or repress enhancer elements in Ewing sarcoma. Cancer Cell. 2014;26:668–81.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Pediatrics, University Clinic of Navarra IdiSNA, Navarra Institute for Health Research, Pio Xii 36, Pamplona, Navarra, 31008, Spain

    Ana Patiño-García PhD

  2. Pediatrics Laboratory, University Clinic of Navarra, Pamplona, Navarra, Spain

    Marta Zalacain-Díez PhD

  3. Program in Solid Tumors and Biomarkers, Center for Applied Medical Research (CIMA), Pamplona, Spain

    Fernando Lecanda PhD

Authors
  1. Ana Patiño-García PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Marta Zalacain-Díez PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Fernando Lecanda PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Ana Patiño-García PhD .

Editor information

Editors and Affiliations

  1. Department of Orthopaedic Surgery, University of Navarra, Pamplona, Navarra, Spain

    Mikel San-Julian

Rights and permissions

Reprints and permissions

Copyright information

© 2016 Springer International Publishing Switzerland

About this chapter

Cite this chapter

Patiño-García, A., Zalacain-Díez, M., Lecanda, F. (2016). Molecular Biology of Pediatric Bone Sarcomas. In: San-Julian, M. (eds) Cañadell's Pediatric Bone Sarcomas. Springer, Cham. https://doi.org/10.1007/978-3-319-24220-0_3

Download citation

  • DOI: https://doi.org/10.1007/978-3-319-24220-0_3

  • Published:

  • Publisher Name: Springer, Cham

  • Print ISBN: 978-3-319-24218-7

  • Online ISBN: 978-3-319-24220-0

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics

Search

Navigation