Skip to main content

Advertisement

SpringerLink
Log in

Genetic aberrations and molecular biology of skull base chordoma and chondrosarcoma

  • Review Article
  • Published:
Brain Tumor Pathology Aims and scope Submit manuscript

Abstract

Chordomas and chondrosarcomas are two major malignant bone neoplasms located at the skull base. These tumors are rarely metastatic, but can be locally invasive and resistant to conventional chemotherapies and radiotherapies. Accordingly, therapeutic approaches for the treatment of these tumors can be difficult. Additionally, their location at the skull base makes them problematic. Although accurate diagnosis of these tumors is important because of their distinct prognoses, distinguishing between these tumor types is difficult due to overlapping radiological and histopathological findings. However, recent accumulation of molecular and genetic studies, including extracranial location analysis, has provided us clues for accurate diagnosis. In this report, we review the genetic aberrations and molecular biology of these two tumor types. Among the abundant genetic features of these tumors, brachyury immunohistochemistry and direct sequencing of IDH1/2 are simple and useful techniques that can be used to distinguish between these tumors. Although it is still unclear why these tumors, which have such distinct genetic backgrounds, show similar histopathological findings, comparison of their genetic backgrounds could provide essential information.

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

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Almefty K, Pravdenkova S, Colli BO, Al-Mefty O, Gokden M (2007) Chordoma and chondrosarcoma: similar, but quite different, skull base tumors. Cancer 110:2457–2467. doi:10.1002/cncr.23073

    Article  PubMed  Google Scholar 

  2. Bohman LE, Koch M, Bailey RL, Alonso-Basanta M, Lee JY (2014) Skull base chordoma and chondrosarcoma: influence of clinical and demographic factors on prognosis—a SEER analysis. World Neurosurg. doi:10.1016/j.wneu.2014.07.005

    PubMed  Google Scholar 

  3. Fletcher CDM, Bridge JA, Hogendoorn P, Mertens F (2013) WHO classification of tumours of soft tissue and bone. Fourth Edition. IARC, Lyon

    Google Scholar 

  4. Rosenberg AE, Nielsen GP, Keel SB, Renard LG, Fitzek MM, Munzenrider JE, Liebsch NJ (1999) Chondrosarcoma of the base of the skull: a clinicopathologic study of 200 cases with emphasis on its distinction from chordoma. Am J Surg Pathol 23:1370–1378

    Article  CAS  PubMed  Google Scholar 

  5. Healey JH, Lane JM (1989) Chordoma: a critical review of diagnosis and treatment. Orthop Clin North Am 20:417–426

    CAS  PubMed  Google Scholar 

  6. Brain Tumor Registry of Japan (2009) Report of Brain Tumor Registry of Japan (1984–2000). Neurol Medico-Chir 49 Suppl: PS1–96

    Google Scholar 

  7. McMaster ML, Goldstein AM, Bromley CM, Ishibe N, Parry DM (2001) Chordoma: incidence and survival patterns in the United States, 1973–1995. Cancer Causes Control 12:1–11

    Article  CAS  PubMed  Google Scholar 

  8. Yang XR, Ng D, Alcorta DA, Liebsch NJ, Sheridan E, Li S, Goldstein AM, Parry DM, Kelley MJ (2009) T (brachyury) gene duplication confers major susceptibility to familial chordoma. Nat Genet 41:1176–1178. doi:10.1038/ng.454

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Walcott BP, Nahed BV, Mohyeldin A, Coumans JV, Kahle KT, Ferreira MJ (2012) Chordoma: current concepts, management, and future directions. Lancet Oncol 13:e69–e76. doi:10.1016/S1470-2045(11)70337-0

    Article  PubMed  Google Scholar 

  10. Favre J, Deruaz JP, Uske A, de Tribolet N (1994) Skull base chordomas: presentation of six cases and review of the literature. J Clin Neurosci 1:7–18

    Article  CAS  PubMed  Google Scholar 

  11. Horbinski C, Oakley GJ, Cieply K, Mantha GS, Nikiforova MN, Dacic S, Seethala RR (2010) The prognostic value of Ki-67, p53, epidermal growth factor receptor, 1p36, 9p21, 10q23, and 17p13 in skull base chordomas. Arch Pathol Lab Med 134:1170–1176. doi:10.1043/2009-0380-OA.1

    PubMed  PubMed Central  Google Scholar 

  12. Kitamura Y, Sasaki H, Kimura T, Miwa T, Takahashi S, Kawase T, Yoshida K (2013) Molecular and clinical risk factors for recurrence of skull base chordomas: gain on chromosome 2p, expression of brachyury, and lack of irradiation negatively correlate with patient prognosis. J Neuropathol Exp Neurol 72:816–823. doi:10.1097/NEN.0b013e3182a065d0

    Article  CAS  PubMed  Google Scholar 

  13. Takahashi S, Kawase T, Yoshida K, Hasegawa A, Mizoe JE (2009) Skull base chordomas: efficacy of surgery followed by carbon ion radiotherapy. Acta Neurochir (Wien) 151:759–769. doi:10.1007/s00701-009-0383-5

    Article  Google Scholar 

  14. Clark FH (1934) Linkage studies of Brachyury (Short Tail) in the house mouse. Proc Natl Acad Sci USA 20:276–279

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Zhu J, Kwan KM, Mackem S (2016) Putative oncogene Brachyury (T) is essential to specify cell fate but dispensable for notochord progenitor proliferation and EMT. Proc Natl Acad Sci USA 113:3820–3825. doi:10.1073/pnas.1601252113

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Fernando RI, Litzinger M, Trono P, Hamilton DH, Schlom J, Palena C (2010) The T-box transcription factor Brachyury promotes epithelial-mesenchymal transition in human tumor cells. J Clin Invest 120:533–544. doi:10.1172/JCI38379

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Palena C, Fernando RI, Litzinger MT, Hamilton DH, Huang B, Schlom J (2011) Strategies to target molecules that control the acquisition of a mesenchymal-like phenotype by carcinoma cells. Exp Biol Med 236:537–545. doi:10.1258/ebm.2011.010367

    Article  CAS  Google Scholar 

  18. Jambhekar NA, Rekhi B, Thorat K, Dikshit R, Agrawal M, Puri A (2010) Revisiting chordoma with brachyury, a “new age” marker: analysis of a validation study on 51 cases. Arch Pathol Lab Med 134:1181–1187. doi:10.1043/2009-0476-OA.1

    PubMed  Google Scholar 

  19. Miettinen M, Wang Z, Lasota J, Heery C, Schlom J, Palena C (2015) Nuclear brachyury expression is consistent in chordoma, common in germ cell tumors and small cell carcinomas, and rare in other carcinomas and sarcomas: an immunohistochemical study of 5229 cases. Am J Surg Pathol 39:1305–1312. doi:10.1097/PAS.0000000000000462

    Article  PubMed  PubMed Central  Google Scholar 

  20. Oakley GJ, Fuhrer K, Seethala RR (2008) Brachyury, SOX-9, and podoplanin, new markers in the skull base chordoma vs chondrosarcoma differential: a tissue microarray-based comparative analysis. Mod Pathol 21:1461–1469. doi:10.1038/modpathol.2008.144

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Sangoi AR, Karamchandani J, Lane B, Higgins JP, Rouse RV, Brooks JD, McKenney JK (2011) Specificity of brachyury in the distinction of chordoma from clear cell renal cell carcinoma and germ cell tumors: a study of 305 cases. Mod Pathol 24:425–429. doi:10.1038/modpathol.2010.196

    Article  CAS  PubMed  Google Scholar 

  22. Vujovic S, Henderson S, Presneau N, Odell E, Jacques TS, Tirabosco R, Boshoff C, Flanagan AM (2006) Brachyury, a crucial regulator of notochordal development, is a novel biomarker for chordomas. J Pathol 209:157–165. doi:10.1002/path.1969

    Article  CAS  PubMed  Google Scholar 

  23. Pillay N, Plagnol V, Tarpey PS, Lobo SB, Presneau N, Szuhai K, Halai D, Berisha F, Cannon SR, Mead S et al (2012) A common single-nucleotide variant in T is strongly associated with chordoma. Nat Genet 44:1185–1187. doi:10.1038/ng.2419

    Article  CAS  PubMed  Google Scholar 

  24. Presneau N, Shalaby A, Ye H, Pillay N, Halai D, Idowu B, Tirabosco R, Whitwell D, Jacques TS, Kindblom LG et al (2011) Role of the transcription factor T (brachyury) in the pathogenesis of sporadic chordoma: a genetic and functional-based study. J Pathol 223:327–335. doi:10.1002/path.2816

    Article  CAS  PubMed  Google Scholar 

  25. Hsu W, Mohyeldin A, Shah SR, ap Rhys CM, Johnson LF, Sedora-Roman NI, Kosztowski TA, Awad OA, McCarthy EF, Loeb DM et al (2011) Generation of chordoma cell line JHC7 and the identification of Brachyury as a novel molecular target. J Neurosurg 115:760–769. doi:10.3171/2011.5.JNS11185

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Nelson AC, Pillay N, Henderson S, Presneau N, Tirabosco R, Halai D, Berisha F, Flicek P, Stemple DL, Stern CD et al (2012) An integrated functional genomics approach identifies the regulatory network directed by brachyury (T) in chordoma. J Pathol 228:274–285. doi:10.1002/path.4082

    Article  CAS  PubMed  Google Scholar 

  27. Nibu Y, Jose-Edwards DS, Di Gregorio A (2013) From notochord formation to hereditary chordoma: the many roles of Brachyury. Biomed Res Int 2013: 826435 doi:10.1155/2013/826435

    Article  PubMed  PubMed Central  Google Scholar 

  28. Antonelli M, Raso A, Mascelli S, Gessi M, Nozza P, Coli A, Gardiman MP, Arcella A, Massimino M, Buttarelli FR et al (2017) SMARCB1/INI1 involvement in pediatric chordoma: a mutational and immunohistochemical analysis. Am J Surg Pathol 41:56–61. doi:10.1097/PAS.0000000000000741

    Article  PubMed  Google Scholar 

  29. Chavez JA, Nasir Ud D, Memon A, Perry A (2014) Anaplastic chordoma with loss of INI1 and brachyury expression in a 2-year-old girl. Clin Neuropathol 33:418–420. doi:10.5414/NP300724

    Article  PubMed  Google Scholar 

  30. Mobley BC, McKenney JK, Bangs CD, Callahan K, Yeom KW, Schneppenheim R, Hayden MG, Cherry AM, Gokden M, Edwards MS et al (2010) Loss of SMARCB1/INI1 expression in poorly differentiated chordomas. Acta Neuropathol (Berl) 120:745–753. doi:10.1007/s00401-010-0767-x

    Article  CAS  Google Scholar 

  31. Yadav R, Sharma MC, Malgulwar PB, Pathak P, Sigamani E, Suri V, Sarkar C, Kumar A, Singh M, Sharma BS et al (2014) Prognostic value of MIB-1, p53, epidermal growth factor receptor, and INI1 in childhood chordomas. Neuro Oncol 16:372–381. doi:10.1093/neuonc/not228

    Article  CAS  PubMed  Google Scholar 

  32. Hasselblatt M, Thomas C, Hovestadt V, Schrimpf D, Johann P, Bens S, Oyen F, Peetz-Dienhart S, Crede Y, Wefers A et al (2016) Poorly differentiated chordoma with SMARCB1/INI1 loss: a distinct molecular entity with dismal prognosis. Acta Neuropathol 132:149–151. doi:10.1007/s00401-016-1574-9

    Article  PubMed  Google Scholar 

  33. Akhavan-Sigari R, Abili M, Gaab MR, Rohde V, Zafar N, Emami P, Ostertag H (2015) Immunohistochemical expression of receptor tyrosine kinase PDGFR-alpha, c-Met, and EGFR in skull base chordoma. Neurosurg Rev 38: 89–98; discussion 98–89 doi:10.1007/s10143-014-0579-x

    Article  CAS  PubMed  Google Scholar 

  34. Dewaele B, Maggiani F, Floris G, Ampe M, Vanspauwen V, Wozniak A, Debiec-Rychter M, Sciot R (2011) Frequent activation of EGFR in advanced chordomas. Clin Sarcoma Res 1: 4 doi:10.1186/2045-3329-1-4

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Fasig JH, Dupont WD, LaFleur BJ, Olson SJ, Cates JM (2008) Immunohistochemical analysis of receptor tyrosine kinase signal transduction activity in chordoma. Neuropathol Appl Neurobiol 34:95–104. doi:10.1111/j.1365-2990.2007.00873.x

    CAS  PubMed  Google Scholar 

  36. Shalaby A, Presneau N, Ye H, Halai D, Berisha F, Idowu B, Leithner A, Liegl B, Briggs TR, Bacsi K et al (2011) The role of epidermal growth factor receptor in chordoma pathogenesis: a potential therapeutic target. J Pathol 223:336–346. doi:10.1002/path.2818

    Article  CAS  PubMed  Google Scholar 

  37. Tamborini E, Virdis E, Negri T, Orsenigo M, Brich S, Conca E, Gronchi A, Stacchiotti S, Manenti G, Casali PG et al (2010) Analysis of receptor tyrosine kinases (RTKs) and downstream pathways in chordomas. Neuro Oncol 12:776–789. doi:10.1093/neuonc/noq003

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Orzan F, Terreni MR, Longoni M, Boari N, Mortini P, Doglioni C, Riva P (2007) Expression study of the target receptor tyrosine kinase of imatinib mesylate in skull base chordomas. Oncol Rep 18:249–252

    CAS  PubMed  Google Scholar 

  39. Tamborini E, Miselli F, Negri T, Lagonigro MS, Staurengo S, Dagrada GP, Stacchiotti S, Pastore E, Gronchi A, Perrone F et al (2006) Molecular and biochemical analyses of platelet-derived growth factor receptor (PDGFR) B, PDGFRA, and KIT receptors in chordomas. Clin Cancer Res 12:6920–6928. doi:10.1158/1078-0432.CCR-06-1584

    Article  CAS  PubMed  Google Scholar 

  40. Shalaby AA, Presneau N, Idowu BD, Thompson L, Briggs TR, Tirabosco R, Diss TC, Flanagan AM (2009) Analysis of the fibroblastic growth factor receptor-RAS/RAF/MEK/ERK-ETS2/brachyury signalling pathway in chordomas. Mod Pathol 22:996–1005. doi:10.1038/modpathol.2009.63

    Article  CAS  PubMed  Google Scholar 

  41. Park JB, Lee CK, Koh JS, Lee JK, Park EY, Riew KD (2007) Overexpressions of nerve growth factor and its tropomyosin-related kinase A receptor on chordoma cells. Spine (Phila Pa 1976) 32: 1969–1973 doi:10.1097/BRS.0b013e318133fbb5

    Article  PubMed  Google Scholar 

  42. Scheipl S, Froehlich EV, Leithner A, Beham A, Quehenberger F, Mokry M, Stammberger H, Varga PP, Lazary A, Windhager R et al (2012) Does insulin-like growth factor 1 receptor (IGF-1R) targeting provide new treatment options for chordomas? A retrospective clinical and immunohistochemical study. Histopathology 60:999–1003. doi:10.1111/j.1365-2559.2012.04186.x

    Article  PubMed  Google Scholar 

  43. Sommer J, Itani DM, Homlar KC, Keedy VL, Halpern JL, Holt GE, Schwartz HS, Coffin CM, Kelley MJ, Cates JM (2010) Methylthioadenosine phosphorylase and activated insulin-like growth factor-1 receptor/insulin receptor: potential therapeutic targets in chordoma. J Pathol 220:608–617. doi:10.1002/path.2679

    Article  CAS  PubMed  Google Scholar 

  44. Tauziede-Espariat A, Bresson D, Polivka M, Bouazza S, Labrousse F, Aronica E, Pretet JL, Projetti F, Herman P, Salle H et al (2016) Prognostic and therapeutic markers in chordomas: a study of 287 tumors. J Neuropathol Exp Neurol 75:111–120. doi:10.1093/jnen/nlv010

    Article  PubMed  Google Scholar 

  45. Scheipl S, Barnard M, Cottone L, Jorgensen M, Drewry DH, Zuercher WJ, Turlais F, Ye H, Leite AP, Smith JA et al (2016) EGFR inhibitors identified as a potential treatment for chordoma in a focused compound screen. J Pathol 239:320–334. doi:10.1002/path.4729

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Schwab J, Antonescu C, Boland P, Healey J, Rosenberg A, Nielsen P, Iafrate J, Delaney T, Yoon S, Choy E et al (2009) Combination of PI3K/mTOR inhibition demonstrates efficacy in human chordoma. Anticancer Res 29:1867–1871

    CAS  PubMed  Google Scholar 

  47. Presneau N, Shalaby A, Idowu B, Gikas P, Cannon SR, Gout I, Diss T, Tirabosco R, Flanagan AM (2009) Potential therapeutic targets for chordoma: PI3K/AKT/TSC1/TSC2/mTOR pathway. Br J Cancer 100:1406–1414. doi:10.1038/sj.bjc.6605019

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Le LP, Nielsen GP, Rosenberg AE, Thomas D, Batten JM, Deshpande V, Schwab J, Duan Z, Xavier RJ, Hornicek FJ et al (2011) Recurrent chromosomal copy number alterations in sporadic chordomas. PLoS ONE 6:e18846. doi:10.1371/journal.pone.0018846

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Long C, Jiang L, Wei F, Ma C, Zhou H, Yang S, Liu X, Liu Z (2013) Integrated miRNA-mRNA analysis revealing the potential roles of miRNAs in chordomas. PloS one 8:e66676. doi:10.1371/journal.pone.0066676

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Yang C, Hornicek FJ, Wood KB, Schwab JH, Choy E, Mankin H, Duan Z (2010) Blockage of Stat3 with CDDO-Me inhibits tumor cell growth in chordoma. Spine (Phila Pa 1976) 35: 1668–1675 doi:10.1097/BRS.0b013e3181c2d2b4

    Article  Google Scholar 

  51. Yang C, Schwab JH, Schoenfeld AJ, Hornicek FJ, Wood KB, Nielsen GP, Choy E, Mankin H, Duan Z (2009) A novel target for treatment of chordoma: signal transducers and activators of transcription 3. Mol Cancer Ther 8:2597–2605. doi:10.1158/1535-7163.MCT-09-0504

    Article  CAS  PubMed  Google Scholar 

  52. Wang L, Zehir A, Nafa K, Zhou N, Berger MF, Casanova J, Sadowska J, Lu C, Allis CD, Gounder M et al (2016) Genomic aberrations frequently alter chromatin regulatory genes in chordoma. Genes Chromosomes Cancer 55:591–600. doi:10.1002/gcc.22362

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Triana A, Sen C, Wolfe D, Hazan R (2005) Cadherins and catenins in clival chordomas: correlation of expression with tumor aggressiveness. Am J Surg Pathol 29:1422–1434

    Article  PubMed  Google Scholar 

  54. Schoenfeld AJ, Wang X, Wang Y, Hornicek FJ, Nielsen GP, Duan Z, Ferrone S, Schwab JH (2016) CSPG4 as a prognostic biomarker in chordoma. Spine J 16:722–727. doi:10.1016/j.spinee.2015.11.059

    Article  PubMed  Google Scholar 

  55. Diaz RJ, Guduk M, Romagnuolo R, Smith CA, Northcott P, Shih D, Berisha F, Flanagan A, Munoz DG, Cusimano MD et al (2012) High-resolution whole-genome analysis of skull base chordomas implicates FHIT loss in chordoma pathogenesis. Neoplasia 14:788–798

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Sa JK, Lee IH, Hong SD, Kong DS, Nam DH (2016) Genomic and transcriptomic characterization of skull base chordoma. Oncotarget. doi:10.18632/oncotarget.13616

    Google Scholar 

  57. Rinner B, Weinhaeusel A, Lohberger B, Froehlich EV, Pulverer W, Fischer C, Meditz K, Scheipl S, Trajanoski S, Guelly C et al (2013) Chordoma characterization of significant changes of the DNA methylation pattern. PLoS ONE 8:e56609. doi:10.1371/journal.pone.0056609

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Alholle A, Brini AT, Bauer J, Gharanei S, Niada S, Slater A, Gentle D, Maher ER, Jeys L, Grimer R et al (2015) Genome-wide DNA methylation profiling of recurrent and non-recurrent chordomas. Epigenetics 10: 213–220 doi:10.1080/15592294.2015.1006497

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Brandal P, Bjerkehagen B, Danielsen H, Heim S (2005) Chromosome 7 abnormalities are common in chordomas. Cancer Genet Cytogenet 160:15–21. doi:10.1016/j.cancergencyto.2004.11.016

    Article  CAS  PubMed  Google Scholar 

  60. Hallor KH, Staaf J, Jonsson G, Heidenblad M, Vult von Steyern F, Bauer HC, Ijszenga M, Hogendoorn PC, Mandahl N, Szuhai K et al (2008) Frequent deletion of the CDKN2A locus in chordoma: analysis of chromosomal imbalances using array comparative genomic hybridisation. Br J Cancer 98:434–442. doi:10.1038/sj.bjc.6604130

    Article  CAS  PubMed  Google Scholar 

  61. Scheil S, Bruderlein S, Liehr T, Starke H, Herms J, Schulte M, Moller P (2001) Genome-wide analysis of sixteen chordomas by comparative genomic hybridization and cytogenetics of the first human chordoma cell line, U-CH1. Genes Chromosomes Cancer 32: 203–211

    Article  CAS  PubMed  Google Scholar 

  62. Tallini G, Dorfman H, Brys P, Dal Cin P, De Wever I, Fletcher CD, Jonson K, Mandahl N, Mertens F, Mitelman F et al (2002) Correlation between clinicopathological features and karyotype in 100 cartilaginous and chordoid tumours. A report from the Chromosomes and Morphology (CHAMP) Collaborative Study Group. J Pathol 196:194–203. doi:10.1002/path.1023

    Article  PubMed  Google Scholar 

  63. Longoni M, Orzan F, Stroppi M, Boari N, Mortini P, Riva P (2008) Evaluation of 1p36 markers and clinical outcome in a skull base chordoma study. Neuro Oncol 10:52–60. doi:10.1215/15228517-2007-048

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Miozzo M, Dalpra L, Riva P, Volonta M, Macciardi F, Pericotti S, Tibiletti MG, Cerati M, Rohde K, Larizza L et al (2000) A tumor suppressor locus in familial and sporadic chordoma maps to 1p36. Int J Cancer 87:68–72

    Article  CAS  PubMed  Google Scholar 

  65. Riva P, Crosti F, Orzan F, Dalpra L, Mortini P, Parafioriti A, Pollo B, Fuhrman Conti AM, Miozzo M, Larizza L (2003) Mapping of candidate region for chordoma development to 1p36.13 by LOH analysis. Int J Cancer 107:493–497. doi:10.1002/ijc.11421

    Article  CAS  PubMed  Google Scholar 

  66. Sawyer JR, Husain M, Al-Mefty O (2001) Identification of isochromosome 1q as a recurring chromosome aberration in skull base chordomas: a new marker for aggressive tumors? Neurosurg Focus 10:E6

    Article  CAS  PubMed  Google Scholar 

  67. Duan Z, Choy E, Nielsen GP, Rosenberg A, Iafrate J, Yang C, Schwab J, Mankin H, Xavier R, Hornicek FJ (2010) Differential expression of microRNA (miRNA) in chordoma reveals a role for miRNA-1 in Met expression. J Orthop Res 28:746–752. doi:10.1002/jor.21055

    CAS  PubMed  Google Scholar 

  68. Duan Z, Shen J, Yang X, Yang P, Osaka E, Choy E, Cote G, Harmon D, Zhang Y, Nielsen GP et al (2014) Prognostic significance of miRNA-1 (miR-1) expression in patients with chordoma. J Orthop Res 32:695–701. doi:10.1002/jor.22589

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Osaka E, Yang X, Shen JK, Yang P, Feng Y, Mankin HJ, Hornicek FJ, Duan Z (2014) MicroRNA-1 (miR-1) inhibits chordoma cell migration and invasion by targeting slug. J Orthop Res 32:1075–1082. doi:10.1002/jor.22632

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Osaka E, Kelly AD, Spentzos D, Choy E, Yang X, Shen JK, Yang P, Mankin HJ, Hornicek FJ, Duan Z (2015) MicroRNA-155 expression is independently predictive of outcome in chordoma. Oncotarget 6:9125–9139. doi:10.18632/oncotarget.3273

    Article  PubMed  PubMed Central  Google Scholar 

  71. Zou MX, Huang W, Wang XB, Li J, Lv GH, Wang B, Deng YW (2015) Reduced expression of miRNA-1237-3p associated with poor survival of spinal chordoma patients. Eur Spine J 24:1738–1746. doi:10.1007/s00586-015-3927-9

    Article  PubMed  Google Scholar 

  72. Zou MX, Huang W, Wang XB, Lv GH, Li J, Deng YW (2014) Identification of miR-140-3p as a marker associated with poor prognosis in spinal chordoma. Int J Clin Exp Pathol 7:4877–4885

    CAS  PubMed  PubMed Central  Google Scholar 

  73. Gulluoglu S, Tuysuz EC, Kuskucu A, Ture U, Atalay B, Sahin F, Bayrak OF (2016) The potential function of microRNA in chordomas. Gene 585:76–83. doi:10.1016/j.gene.2016.03.032

    Article  CAS  PubMed  Google Scholar 

  74. Mathios D, Ruzevick J, Jackson CM, Xu H, Shah S, Taube JM, Burger PC, McCarthy EF, Quinones-Hinojosa A, Pardoll DM et al (2015) PD-1, PD-L1, PD-L2 expression in the chordoma microenvironment. J Neurooncol 121:251–259. doi:10.1007/s11060-014-1637-5

    Article  CAS  PubMed  Google Scholar 

  75. Feng Y, Shen J, Gao Y, Liao Y, Cote G, Choy E, Chebib I, Mankin H, Hornicek F, Duan Z (2015) Expression of programmed cell death ligand 1 (PD-L1) and prevalence of tumor-infiltrating lymphocytes (TILs) in chordoma. Oncotarget 6:11139–11149. doi:10.18632/oncotarget.3576

    Article  PubMed  PubMed Central  Google Scholar 

  76. Zou MX, Peng AB, Lv GH, Wang XB, Li J, She XL, Jiang Y (2016) Expression of programmed death-1 ligand (PD-L1) in tumor-infiltrating lymphocytes is associated with favorable spinal chordoma prognosis. Am J Transl Res 8:3274–3287

    PubMed  PubMed Central  Google Scholar 

  77. Hof H, Welzel T, Debus J (2006) Effectiveness of cetuximab/gefitinib in the therapy of a sacral chordoma. Onkologie 29:572–574. doi:10.1159/000096283

    PubMed  Google Scholar 

  78. Linden O, Stenberg L, Kjellen E (2009) Regression of cervical spinal cord compression in a patient with chordoma following treatment with cetuximab and gefitinib. Acta Oncol 48:158–159. doi:10.1080/02841860802266672

    Article  PubMed  Google Scholar 

  79. Asklund T, Sandstrom M, Shahidi S, Riklund K, Henriksson R (2014) Durable stabilization of three chordoma cases by bevacizumab and erlotinib. Acta Oncol 53:980–984. doi:10.3109/0284186X.2013.878472

    Article  CAS  PubMed  Google Scholar 

  80. Launay SG, Chetaille B, Medina F, Perrot D, Nazarian S, Guiramand J, Moureau-Zabotto L, Bertucci F (2011) Efficacy of epidermal growth factor receptor targeting in advanced chordoma: case report and literature review. BMC Cancer 11:423. doi:10.1186/1471-2407-11-423

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Singhal N, Kotasek D, Parnis FX (2009) Response to erlotinib in a patient with treatment refractory chordoma. Anticancer Drugs 20:953–955. doi:10.1097/CAD.0b013e328330c7f0

    Article  CAS  PubMed  Google Scholar 

  82. Stacchiotti S, Tamborini E, Lo Vullo S, Bozzi F, Messina A, Morosi C, Casale A, Crippa F, Conca E, Negri T et al (2013) Phase II study on lapatinib in advanced EGFR-positive chordoma. Ann Oncol 24:1931–1936. doi:10.1093/annonc/mdt117

    Article  CAS  PubMed  Google Scholar 

  83. Hindi N, Casali PG, Morosi C, Messina A, Palassini E, Pilotti S, Tamborini E, Radaelli S, Gronchi A, Stacchiotti S (2015) Imatinib in advanced chordoma: a retrospective case series analysis. Eur J Cancer 51:2609–2614. doi:10.1016/j.ejca.2015.07.038

    Article  CAS  PubMed  Google Scholar 

  84. Stacchiotti S, Longhi A, Ferraresi V, Grignani G, Comandone A, Stupp R, Bertuzzi A, Tamborini E, Pilotti S, Messina A et al (2012) Phase II study of imatinib in advanced chordoma. J Clin Oncol 30:914–920. doi:10.1200/JCO.2011.35.3656

    Article  CAS  PubMed  Google Scholar 

  85. Stacchiotti S, Marrari A, Tamborini E, Palassini E, Virdis E, Messina A, Crippa F, Morosi C, Gronchi A, Pilotti S et al (2009) Response to imatinib plus sirolimus in advanced chordoma. Ann Oncol 20:1886–1894. doi:10.1093/annonc/mdp210

    Article  CAS  PubMed  Google Scholar 

  86. Ricci-Vitiani L, Runci D, D’Alessandris QG, Cenci T, Martini M, Bianchi F, Maira G, Stancato L, De Maria R, Larocca LM et al (2013) Chemotherapy of skull base chordoma tailored on responsiveness of patient-derived tumor cells to rapamycin. Neoplasia 15:773–782

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Schuetze SM, Bolejack V, Choy E, Ganjoo KN, Staddon AP, Chow WA, Tawbi HA, Samuels BL, Patel SR, von Mehren M et al (2017) Phase 2 study of dasatinib in patients with alveolar soft part sarcoma, chondrosarcoma, chordoma, epithelioid sarcoma, or solitary fibrous tumor. Cancer 123:90–97. doi:10.1002/cncr.30379

    Article  CAS  PubMed  Google Scholar 

  88. The Chordoma Foundation (2017) Clinical Trials Program https://www.chordomafoundation.org/clinical-trials-program/?utm_source=Chordoma+Foundation+Newsletter&utm_campaign=3bad75d02c-2017_CF_Newsletter_01_Jan_1_26_20171_30_2017&utm_medium=email&utm_term=0_288d805c80-3bad75d02c-86990177. Accessed 2/2/2017

  89. Dorfman HD, Czerniak B (1995) Bone cancers. Cancer 75:203–210

    Article  CAS  PubMed  Google Scholar 

  90. Rigau V, Zouaoui S, Mathieu-Daude H, Darlix A, Maran A, Tretarre B, Bessaoud F, Bauchet F, Attaoua R, Fabbro-Peray P et al (2011) French brain tumor database: 5-year histological results on 25 756 cases. Brain Pathol 21:633–644. doi:10.1111/j.1750-3639.2011.00491.x

    Article  PubMed  Google Scholar 

  91. Bjornsson J, McLeod RA, Unni KK, Ilstrup DM, Pritchard DJ (1998) Primary chondrosarcoma of long bones and limb girdles. Cancer 83:2105–2119

    Article  CAS  PubMed  Google Scholar 

  92. Bovee JV, Hogendoorn PC, Wunder JS, Alman BA (2010) Cartilage tumours and bone development: molecular pathology and possible therapeutic targets. Nat Rev Cancer 10:481–488. doi:10.1038/nrc2869

    Article  CAS  PubMed  Google Scholar 

  93. Arai M, Nobusawa S, Ikota H, Takemura S, Nakazato Y (2012) Frequent IDH1/2 mutations in intracranial chondrosarcoma: a possible diagnostic clue for its differentiation from chordoma. Brain Tumor Pathol 29:201–206. doi:10.1007/s10014-012-0085-1

    Article  CAS  PubMed  Google Scholar 

  94. Kanamori H, Kitamura Y, Kimura T, Yoshida K, Sasaki H (2015) Genetic characterization of skull base chondrosarcomas. J Neurosurg 123:1036–1041. doi:10.3171/2014.12.JNS142059

    Article  PubMed  Google Scholar 

  95. Amary MF, Bacsi K, Maggiani F, Damato S, Halai D, Berisha F, Pollock R, O’Donnell P, Grigoriadis A, Diss T et al (2011) IDH1 and IDH2 mutations are frequent events in central chondrosarcoma and central and periosteal chondromas but not in other mesenchymal tumours. J Pathol 224:334–343. doi:10.1002/path.2913

    Article  CAS  PubMed  Google Scholar 

  96. Tarpey PS, Behjati S, Cooke SL, Van Loo P, Wedge DC, Pillay N, Marshall J, O’Meara S, Davies H, Nik-Zainal S et al (2013) Frequent mutation of the major cartilage collagen gene COL2A1 in chondrosarcoma. Nat Genet 45:923–926. doi:10.1038/ng.2668

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Li L, Paz AC, Wilky BA, Johnson B, Galoian K, Rosenberg A, Hu G, Tinoco G, Bodamer O, Trent JC (2015) Treatment with a small molecule mutant IDH1 inhibitor suppresses tumorigenic activity and decreases production of the oncometabolite 2-hydroxyglutarate in human chondrosarcoma cells. PLoS ONE 10:e0133813. doi:10.1371/journal.pone.0133813

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  98. Dang L, Yen K, Attar EC (2016) IDH mutations in cancer and progress toward development of targeted therapeutics. Ann Oncol 27:599–608. doi:10.1093/annonc/mdw013

    Article  CAS  PubMed  Google Scholar 

  99. Song J, Zhu J, Zhao Q, Tian B (2015) Gefitinib causes growth arrest and inhibition of metastasis in human chondrosarcoma cells. J BUON 20:894–901

    PubMed  Google Scholar 

  100. Zhang YX, van Oosterwijk JG, Sicinska E, Moss S, Remillard SP, van Wezel T, Buhnemann C, Hassan AB, Demetri GD, Bovee JV et al (2013) Functional profiling of receptor tyrosine kinases and downstream signaling in human chondrosarcomas identifies pathways for rational targeted therapy. Clin Cancer Res 19:3796–3807. doi:10.1158/1078-0432.CCR-12-3647

    Article  CAS  PubMed  Google Scholar 

  101. Sulzbacher I, Birner P, Trieb K, Muhlbauer M, Lang S, Chott A (2001) Platelet-derived growth factor-alpha receptor expression supports the growth of conventional chondrosarcoma and is associated with adverse outcome. Am J Surg Pathol 25:1520–1527

    Article  CAS  PubMed  Google Scholar 

  102. Ho L, Stojanovski A, Whetstone H, Wei QX, Mau E, Wunder JS, Alman B (2009) Gli2 and p53 cooperate to regulate IGFBP-3- mediated chondrocyte apoptosis in the progression from benign to malignant cartilage tumors. Cancer Cell 16:126–136. doi:10.1016/j.ccr.2009.05.013

    Article  CAS  PubMed  Google Scholar 

  103. Matsumura T, Whelan MC, Li XQ, Trippel SB (2000) Regulation by IGF-I and TGF-beta1 of Swarm-rat chondrosarcoma chondrocytes. J Orthop Res 18:351–355. doi:10.1002/jor.1100180305

    Article  CAS  PubMed  Google Scholar 

  104. Sun X, Charbonneau C, Wei L, Chen Q, Terek RM (2015) miR-181a targets RGS16 to promote chondrosarcoma growth, angiogenesis, and metastasis. Mol Cancer Res 13:1347–1357. doi:10.1158/1541-7786.MCR-14-0697

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Tzeng HE, Chen PC, Lin KW, Lin CY, Tsai CH, Han SM, Teng CL, Hwang WL, Wang SW, Tang CH (2015) Basic fibroblast growth factor induces VEGF expression in chondrosarcoma cells and subsequently promotes endothelial progenitor cell-primed angiogenesis. Clinical Sci 129:147–158. doi:10.1042/CS20140390

    Article  CAS  Google Scholar 

  106. Peterse EF, Cleven AH, De Jong Y, Briaire-de Bruijn I, Fletcher JA, Danen EH, Cleton-Jansen AM, Bovee JV (2016) No preclinical rationale for IGF1R directed therapy in chondrosarcoma of bone. BMC Cancer 16:475. doi:10.1186/s12885-016-2522-8

    Article  PubMed  PubMed Central  Google Scholar 

  107. Asp J, Sangiorgi L, Inerot SE, Lindahl A, Molendini L, Benassi MS, Picci P (2000) Changes of the p16 gene but not the p53 gene in human chondrosarcoma tissues. Int J Cancer 85:782–786

    Article  CAS  PubMed  Google Scholar 

  108. Schrage YM, Lam S, Jochemsen AG, Cleton-Jansen AM, Taminiau AH, Hogendoorn PC, Bovee JV (2009) Central chondrosarcoma progression is associated with pRb pathway alterations: CDK4 down-regulation and p16 overexpression inhibit cell growth in vitro. J Cell Mol Med 13:2843–2852. doi:10.1111/j.1582-4934.2008.00406.x

    Article  CAS  PubMed  Google Scholar 

  109. van Beerendonk HM, Rozeman LB, Taminiau AH, Sciot R, Bovee JV, Cleton-Jansen AM, Hogendoorn PC (2004) Molecular analysis of the INK4A/INK4A-ARF gene locus in conventional (central) chondrosarcomas and enchondromas: indication of an important gene for tumour progression. J Pathol 202:359–366. doi:10.1002/path.1517

    Article  PubMed  CAS  Google Scholar 

  110. Tiet TD, Hopyan S, Nadesan P, Gokgoz N, Poon R, Lin AC, Yan T, Andrulis IL, Alman BA, Wunder JS (2006) Constitutive hedgehog signaling in chondrosarcoma up-regulates tumor cell proliferation. Am J Pathol 168:321–330. doi:10.2353/ajpath.2006.050001

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Campbell VT, Nadesan P, Ali SA, Wang CY, Whetstone H, Poon R, Wei Q, Keilty J, Proctor J, Wang LW et al (2014) Hedgehog pathway inhibition in chondrosarcoma using the smoothened inhibitor IPI-926 directly inhibits sarcoma cell growth. Mol Cancer Ther 13:1259–1269. doi:10.1158/1535-7163.MCT-13-0731

    Article  CAS  PubMed  Google Scholar 

  112. Speetjens FM, de Jong Y, Gelderblom H, Bovee JV (2016) Molecular oncogenesis of chondrosarcoma: impact for targeted treatment. Curr Opin Oncol 28:314–322. doi:10.1097/CCO.0000000000000300

    Article  CAS  PubMed  Google Scholar 

  113. Jiang D, Zheng X, Shan W, Shan Y (2016) The overexpression of miR-30a affects cell proliferation of chondrosarcoma via targeting Runx2. Tumour Biol 37:5933–5940. doi:10.1007/s13277-015-4454-3

    Article  CAS  PubMed  Google Scholar 

  114. Brown RE (2004) Morphoproteomic portrait of the mTOR pathway in mesenchymal chondrosarcoma. Ann Clin Lab Sci 34:397–399

    PubMed  Google Scholar 

  115. Schrage YM, Briaire-de Bruijn IH, de Miranda NF, van Oosterwijk J, Taminiau AH, van Wezel T, Hogendoorn PC, Bovee JV (2009) Kinome profiling of chondrosarcoma reveals SRC-pathway activity and dasatinib as option for treatment. Cancer Res 69:6216–6222. doi:10.1158/0008-5472.CAN-08-4801

    Article  CAS  PubMed  Google Scholar 

  116. Perez J, Decouvelaere AV, Pointecouteau T, Pissaloux D, Michot JP, Besse A, Blay JY, Dutour A (2012) Inhibition of chondrosarcoma growth by mTOR inhibitor in an in vivo syngeneic rat model. PLoS ONE 7:e32458. doi:10.1371/journal.pone.0032458

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Kubo T, Sugita T, Shimose S, Matsuo T, Arihiro K, Ochi M (2008) Expression of hypoxia-inducible factor-1alpha and its relationship to tumour angiogenesis and cell proliferation in cartilage tumours. J Bone Joint Surg Br 90:364–370. doi:10.1302/0301-620X.90B3.19806

    Article  CAS  PubMed  Google Scholar 

  118. Oshiro Y, Chaturvedi V, Hayden D, Nazeer T, Johnson M, Johnston DA, Ordonez NG, Ayala AG, Czerniak B (1998) Altered p53 is associated with aggressive behavior of chondrosarcoma: a long term follow-up study. Cancer 83:2324–2334

    Article  CAS  PubMed  Google Scholar 

  119. van Oosterwijk JG, Herpers B, Meijer D, Briaire-de Bruijn IH, Cleton-Jansen AM, Gelderblom H, van de Water B, Bovee JV (2012) Restoration of chemosensitivity for doxorubicin and cisplatin in chondrosarcoma in vitro: BCL-2 family members cause chemoresistance. Ann Oncol 23:1617–1626. doi:10.1093/annonc/mdr512

    Article  PubMed  Google Scholar 

  120. Fitzgerald MP, Gourronc F, Teoh ML, Provenzano MJ, Case AJ, Martin JA, Domann FE (2011) Human chondrosarcoma cells acquire an epithelial-like gene expression pattern via an epigenetic switch: evidence for mesenchymal-epithelial transition during sarcomagenesis. Sarcoma 2011: 598218 doi:10.1155/2011/598218

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  121. Bui C, Ouzzine M, Talhaoui I, Sharp S, Prydz K, Coughtrie MW, Fournel-Gigleux S (2010) Epigenetics: methylation-associated repression of heparan sulfate 3-O-sulfotransferase gene expression contributes to the invasive phenotype of H-EMC-SS chondrosarcoma cells. FASEB J 24:436–450. doi:10.1096/fj.09-136291

    Article  CAS  PubMed  Google Scholar 

  122. Jin Z, Han YX, Han XR (2013) Loss of RUNX3 expression may contribute to poor prognosis in patients with chondrosarcoma. J Mol Histol 44:645–652. doi:10.1007/s10735-013-9511-x

    Article  CAS  PubMed  Google Scholar 

  123. Hallor KH, Staaf J, Bovee JV, Hogendoorn PC, Cleton-Jansen AM, Knuutila S, Savola S, Niini T, Brosjo O, Bauer HC et al (2009) Genomic profiling of chondrosarcoma: chromosomal patterns in central and peripheral tumors. Clin Cancer Res 15:2685–2694. doi:10.1158/1078-0432.CCR-08-2330

    Article  CAS  PubMed  Google Scholar 

  124. Hameed M, Ulger C, Yasar D, Limaye N, Kurvathi R, Streck D, Benevenia J, Patterson F, Dermody JJ, Toruner GA (2009) Genome profiling of chondrosarcoma using oligonucleotide array-based comparative genomic hybridization. Cancer Genet Cytogenet 192:56–59. doi:10.1016/j.cancergencyto.2009.03.009

    Article  CAS  PubMed  Google Scholar 

  125. Larramendy ML, Mandahl N, Mertens F, Blomqvist C, Kivioja AH, Karaharju E, Valle J, Bohling T, Tarkkanen M, Rydholm A et al (1999) Clinical significance of genetic imbalances revealed by comparative genomic hybridization in chondrosarcomas. Hum Pathol 30:1247–1253

    Article  CAS  PubMed  Google Scholar 

  126. Larramendy ML, Tarkkanen M, Valle J, Kivioja AH, Ervasti H, Karaharju E, Salmivalli T, Elomaa I, Knuutila S (1997) Gains, losses, and amplifications of DNA sequences evaluated by comparative genomic hybridization in chondrosarcomas. Am J Pathol 150:685–691

    CAS  PubMed  PubMed Central  Google Scholar 

  127. Ozaki T, Wai D, Schafer KL, Lindner N, Bocker W, Winkelmann W, Dockhorn-Dworniczak B, Poremba C (2004) Comparative genomic hybridization in cartilaginous tumors. Anticancer Res 24:1721–1725

    CAS  PubMed  Google Scholar 

  128. Rozeman LB, Szuhai K, Schrage YM, Rosenberg C, Tanke HJ, Taminiau AH, Cleton-Jansen AM, Bovee JV, Hogendoorn PC (2006) Array-comparative genomic hybridization of central chondrosarcoma: identification of ribosomal protein S6 and cyclin-dependent kinase 4 as candidate target genes for genomic aberrations. Cancer 107:380–388. doi:10.1002/cncr.22001

    Article  CAS  PubMed  Google Scholar 

  129. Lu N, Lin T, Wang L, Qi M, Liu Z, Dong H, Zhang X, Zhai C, Wang Y, Liu L et al (2015) Association of SOX4 regulated by tumor suppressor miR-30a with poor prognosis in low-grade chondrosarcoma. Tumour Biol 36:3843–3852. doi:10.1007/s13277-014-3026-2

    Article  CAS  PubMed  Google Scholar 

  130. Yoshitaka T, Kawai A, Miyaki S, Numoto K, Kikuta K, Ozaki T, Lotz M, Asahara H (2013) Analysis of microRNAs expressions in chondrosarcoma. J Orthop Res 31:1992–1998. doi:10.1002/jor.22457

    Article  CAS  PubMed  Google Scholar 

  131. Li J, Wang L, Liu Z, Zu C, Xing F, Yang P, Yang Y, Dang X, Wang K (2015) MicroRNA-494 inhibits cell proliferation and invasion of chondrosarcoma cells in vivo and in vitro by directly targeting SOX9. Oncotarget 6:26216–26229. doi:10.18632/oncotarget.4460

    Article  PubMed  PubMed Central  Google Scholar 

  132. Mak IW, Singh S, Turcotte R, Ghert M (2015) The epigenetic regulation of SOX9 by miR-145 in human chondrosarcoma. J Cell Biochem 116:37–44. doi:10.1002/jcb.24940

    Article  CAS  PubMed  Google Scholar 

  133. Tsai CH, Tsai HC, Huang HN, Hung CH, Hsu CJ, Fong YC, Hsu HC, Huang YL, Tang CH (2015) Resistin promotes tumor metastasis by down-regulation of miR-519d through the AMPK/p38 signaling pathway in human chondrosarcoma cells. Oncotarget 6:258–270. doi:10.18632/oncotarget.2724

    PubMed  Google Scholar 

  134. Aili A, Chen Y, Zhang H (2016) MicroRNA10b suppresses the migration and invasion of chondrosarcoma cells by targeting brain-derived neurotrophic factor. Mol Med Rep 13: 441–446 doi:10.3892/mmr.2015.4506

    CAS  PubMed  Google Scholar 

  135. Kostine M, Cleven AH, de Miranda NF, Italiano A, Cleton-Jansen AM, Bovee JV (2016) Analysis of PD-L1, T-cell infiltrate and HLA expression in chondrosarcoma indicates potential for response to immunotherapy specifically in the dedifferentiated subtype. Mod Pathol 29:1028–1037. doi:10.1038/modpathol.2016.108

    Article  CAS  PubMed  Google Scholar 

  136. Paoluzzi L, Cacavio A, Ghesani M, Karambelkar A, Rapkiewicz A, Weber J, Rosen G (2016) Response to anti-PD1 therapy with nivolumab in metastatic sarcomas. Clin Sarcoma Res 6: 24 doi:10.1186/s13569-016-0064-0

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. Grignani G, Palmerini E, Stacchiotti S, Boglione A, Ferraresi V, Frustaci S, Comandone A, Casali PG, Ferrari S, Aglietta M (2011) A phase 2 trial of imatinib mesylate in patients with recurrent nonresectable chondrosarcomas expressing platelet-derived growth factor receptor-alpha or -beta: an Italian Sarcoma Group study. Cancer 117:826–831. doi:10.1002/cncr.25632

    Article  CAS  PubMed  Google Scholar 

  138. Schwartz GK, Tap WD, Qin LX, Livingston MB, Undevia SD, Chmielowski B, Agulnik M, Schuetze SM, Reed DR, Okuno SH et al (2013) Cixutumumab and temsirolimus for patients with bone and soft-tissue sarcoma: a multicentre, open-label, phase 2 trial. Lancet Oncol 14:371–382. doi:10.1016/S1470-2045(13)70049-4

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  139. Thornton KA, Chen AR, Trucco MM, Shah P, Wilky BA, Gul N, Carrera-Haro MA, Ferreira MF, Shafique U, Powell JD et al (2013) A dose-finding study of temsirolimus and liposomal doxorubicin for patients with recurrent and refractory bone and soft tissue sarcoma. Int J Cancer 133:997–1005. doi:10.1002/ijc.28083

    Article  CAS  PubMed  Google Scholar 

  140. Italiano A, Le Cesne A, Bellera C, Piperno-Neumann S, Duffaud F, Penel N, Cassier P, Domont J, Takebe N, Kind M et al (2013) GDC-0449 in patients with advanced chondrosarcomas: a French Sarcoma Group/US and French National Cancer Institute Single-Arm Phase II Collaborative Study. Ann Oncol 24:2922–2926. doi:10.1093/annonc/mdt391

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  141. The U.S. National Institutes of Health (2017) SARC028: A phase II study of the anti-PD1 antibody pembrolizumab (MK-3475) in patients with advanced sarcomas https://clinicaltrials.gov/ct2/show/NCT02301039. Accessed 30 Jan 2017

  142. The U.S. National Institutes of Health (2017) A phase II study evaluating efficacy and safety of regorafenib in patients with metastatic bone sarcomas (REGOBONE) https://clinicaltrials.gov/ct2/show/NCT02389244. Accessed 2 Feb 2017

  143. The U.S. National Institutes of Health (2017) Study of pazopanib in the treatment of surgically unresectable or metastatic chondrosarcoma https://clinicaltrials.gov/ct2/show/NCT01330966. Accessed 2 Feb 2017

  144. Bernstein-Molho R, Kollender Y, Issakov J, Bickels J, Dadia S, Flusser G, Meller I, Sagi-Eisenberg R, Merimsky O (2012) Clinical activity of mTOR inhibition in combination with cyclophosphamide in the treatment of recurrent unresectable chondrosarcomas. Cancer Chemother Pharmacol 70:855–860. doi:10.1007/s00280-012-1968-x

    Article  CAS  PubMed  Google Scholar 

  145. Louis DN, Ohgaki H, Wiestler OD, Cavenee WK (2016) World Health Organization histological classification of tumours of the central nervous system. International Agency for Research on Cancer, Lyon

    Google Scholar 

  146. Lagonigro MS, Tamborini E, Negri T, Staurengo S, Dagrada GP, Miselli F, Gabanti E, Greco A, Casali PG, Carbone A et al (2006) PDGFRalpha, PDGFRbeta and KIT expression/activation in conventional chondrosarcoma. J Pathol 208:615–623. doi:10.1002/path.1945

    Article  CAS  PubMed  Google Scholar 

  147. Zhu Z, Wang CP, Zhang YF, Nie L (2014) MicroRNA-100 resensitizes resistant chondrosarcoma cells to cisplatin through direct targeting of mTOR. Asian Pac J Cancer Prev 15: 917–923

    Article  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Neurosurgery, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan

    Yohei Kitamura, Hikaru Sasaki & Kazunari Yoshida

Authors
  1. Yohei Kitamura
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Hikaru Sasaki
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Kazunari Yoshida
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Yohei Kitamura.

Ethics declarations

Disclosure

The authors have no personal, financial, or institutional interest in any of the drugs, materials, or devices described in this article.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Kitamura, Y., Sasaki, H. & Yoshida, K. Genetic aberrations and molecular biology of skull base chordoma and chondrosarcoma. Brain Tumor Pathol 34, 78–90 (2017). https://doi.org/10.1007/s10014-017-0283-y

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10014-017-0283-y

Keywords

Search

Navigation