Journal of Korean Neurosurgical Society

The Korean Neurosurgical Society (대한신경외과학회)
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The Similarities and Differences between Intracranial and Spinal Ependymomas : A Review from a Genetic Research Perspective

  • Lee, Chang-Hyun (Department of Neurosurgery, Ilsan Paik Hospital, Inje University College of Medicine) ;
  • Chung, Chun Kee (Department of Neurosurgery, Seoul National University Hospital) ;
  • Ohn, Jung Hun (Bioinformatics, Samsung Gene Institute, Samsung Medical Center) ;
  • Kim, Chi Heon (Department of Neurosurgery, Seoul National University Hospital)
  • Received : 2015.11.20
  • Accepted : 2016.01.01
  • Published : 2016.03.01
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Abstract

Ependymomas occur in both the brain and spine. The prognosis of these tumors sometimes differs for different locations. The genetic landscape of ependymoma is very heterogeneous despite the similarity of histopathologic findings. In this review, we describe the genetic differences between spinal ependymomas and their intracranial counterparts to better understand their prognosis. From the literature review, many studies have reported that spinal cord ependymoma might be associated with NF2 mutation, NEFL overexpression, Merlin loss, and 9q gain. In myxopapillary ependymoma, NEFL and HOXB13 overexpression were reported to be associated. Prior studies have identified HIC-1 methylation, 4.1B deletion, and 4.1R loss as common features in intracranial ependymoma. Supratentorial ependymoma is usually characterized by NOTCH-1 mutation and p75 expression. TNC mutation, no hypermethylation of RASSF1A, and GFAP/NeuN expression may be diagnostic clues of posterior fossa ependymoma. Although MEN1, TP53, and PTEN mutations are rarely reported in ependymoma, they may be related to a poor prognosis, such as recurrence or metastasis. Spinal ependymoma has been found to be quite different from intracranial ependymoma in genetic studies, and the favorable prognosis in spinal ependymoma may be the result of the genetic differences. A more detailed understanding of these various genetic aberrations may enable the identification of more specific prognostic markers as well as the development of customized targeted therapies.

Keywords

References

  1. Ahmad ZK, Brown CM, Cueva RA, Ryan AF, Doherty JK : ErbB expression, activation, and inhibition with lapatinib and tyrphostin (AG825) in human vestibular schwannomas. Otol Neurotol 32 : 841-847, 2011 https://doi.org/10.1097/MAO.0b013e31821f7d88
  2. Andreiuolo F, Puget S, Peyre M, Dantas-Barbosa C, Boddaert N, Philippe C, et al. : Neuronal differentiation distinguishes supratentorial and infratentorial childhood ependymomas. Neuro Oncol 12 : 1126-1134, 2010 https://doi.org/10.1093/neuonc/noq074
  3. Athanasiou A, Perunovic B, Quilty RD, Gorgoulis VG, Kittas C, Love S : Expression of mos in ependymal gliomas. Am J Clin Pathol 120 : 699-705, 2003 https://doi.org/10.1309/DL2TLDJG7JB1BQ72
  4. Barton VN, Donson AM, Kleinschmidt-DeMasters BK, Birks DK, Handler MH, Foreman NK : Unique molecular characteristics of pediatric myxopapillary ependymoma. Brain Pathol 20 : 560-570, 2010 https://doi.org/10.1111/j.1750-3639.2009.00333.x
  5. Bettegowda C, Agrawal N, Jiao Y, Wang Y, Wood LD, Rodriguez FJ, et al. : Exomic sequencing of four rare central nervous system tumor types. Oncotarget 4 : 572-583, 2013 https://doi.org/10.18632/oncotarget.964
  6. de Bont JM, Packer RJ, Michiels EM, den Boer ML, Pieters R : Biological background of pediatric medulloblastoma and ependymoma : a review from a translational research perspective. Neuro Oncol 10 : 1040-1060, 2008 https://doi.org/10.1215/15228517-2008-059
  7. Ebert C, von Haken M, Meyer-Puttlitz B, Wiestler OD, Reifenberger G, Pietsch T, et al. : Molecular genetic analysis of ependymal tumors. NF2 mutations and chromosome 22q loss occur preferentially in intramedullary spinal ependymomas. Am J Pathol 155 : 627-632, 1999 https://doi.org/10.1016/S0002-9440(10)65158-9
  8. Fink KL, Rushing EJ, Schold SC Jr, Nisen PD : Infrequency of p53 gene mutations in ependymomas. J Neurooncol 27 : 111-115, 1996
  9. Garcia C, Gutmann DH : Nf2/Merlin controls spinal cord neural progenitor function in a Rac1/ErbB2-dependent manner. PLoS One 9 : e97320, 2014 https://doi.org/10.1371/journal.pone.0097320
  10. Gilbertson RJ, Bentley L, Hernan R, Junttila TT, Frank AJ, Haapasalo H, et al. : ERBB receptor signaling promotes ependymoma cell proliferation and represents a potential novel therapeutic target for this disease. Clin Cancer Res 8 : 3054-3064, 2002
  11. Gonzalez-Gomez P, Bello MJ, Alonso ME, Arjona D, Lomas J, de Campos JM, et al. : CpG island methylation status and mutation analysis of the RB1 gene essential promoter region and protein-binding pocket domain in nervous system tumours. Br J Cancer 88 : 109-114, 2003 https://doi.org/10.1038/sj.bjc.6600737
  12. Gupta RK, Sharma MC, Suri V, Kakkar A, Singh M, Sarkar C : Study of chromosome 9q gain, Notch pathway regulators and Tenascin-C in ependymomas. J Neurooncol 116 : 267-274, 2014 https://doi.org/10.1007/s11060-013-1287-z
  13. Hagel C, Treszl A, Fehlert J, Harder J, von Haxthausen F, Kern M, et al. : Supra- and infratentorial pediatric ependymomas differ significantly in NeuN, p75 and GFAP expression. J Neurooncol 112 : 191-197, 2013 https://doi.org/10.1007/s11060-013-1062-1
  14. Hamilton DW, Lusher ME, Lindsey JC, Ellison DW, Clifford SC : Epigenetic inactivation of the RASSF1A tumour suppressor gene in ependymoma. Cancer Lett 227 : 75-81, 2005 https://doi.org/10.1016/j.canlet.2004.11.044
  15. Huang B, Starostik P, Kuhl J, Tonn JC, Roggendorf W : Loss of heterozygosity on chromosome 22 in human ependymomas. Acta Neuropathol 103 : 415-420, 2002 https://doi.org/10.1007/s00401-001-0479-3
  16. Huang B, Starostik P, Schraut H, Krauss J, Sorensen N, Roggendorf W : Human ependymomas reveal frequent deletions on chromosomes 6 and 9. Acta Neuropathol 106 : 357-362, 2003 https://doi.org/10.1007/s00401-003-0739-5
  17. Johnson RA, Wright KD, Poppleton H, Mohankumar KM, Finkelstein D, Pounds SB, et al. : Cross-species genomics matches driver mutations and cell compartments to model ependymoma. Nature 466 : 632-636, 2010 https://doi.org/10.1038/nature09173
  18. Kilday JP, Rahman R, Dyer S, Ridley L, Lowe J, Coyle B, et al. : Pediatric ependymoma : biological perspectives. Mol Cancer Res 7 : 765-786, 2009 https://doi.org/10.1158/1541-7786.MCR-08-0584
  19. Korshunov A, Witt H, Hielscher T, Benner A, Remke M, Ryzhova M, et al. : Molecular staging of intracranial ependymoma in children and adults. J Clin Oncol 28 : 3182-3190, 2010 https://doi.org/10.1200/JCO.2009.27.3359
  20. Kraus JA, de Millas W, Sorensen N, Herbold C, Schichor C, Tonn JC, et al. : Indications for a tumor suppressor gene at 22q11 involved in the pathogenesis of ependymal tumors and distinct from hSNF5/INI1. Acta Neuropathol 102 : 69-74, 2001
  21. Lamszus K, Lachenmayer L, Heinemann U, Kluwe L, Finckh U, Hoppner W, et al. : Molecular genetic alterations on chromosomes 11 and 22 in ependymomas. Int J Cancer 91 : 803-808, 2001 https://doi.org/10.1002/1097-0215(200002)9999:9999<::AID-IJC1134>3.0.CO;2-P
  22. Magrassi L, Conti L, Lanterna A, Zuccato C, Marchionni M, Cassini P, et al. : Shc3 affects human high-grade astrocytomas survival. Oncogene 24 : 5198-5206, 2005 https://doi.org/10.1038/sj.onc.1208708
  23. Magrassi L, Marziliano N, Inzani F, Cassini P, Chiaranda I, Skrap M, et al. : EDG3 and SHC3 on chromosome 9q22 are co-amplified in human ependymomas. Cancer Lett 290 : 36-42, 2010 https://doi.org/10.1016/j.canlet.2009.08.023
  24. Modena P, Lualdi E, Facchinetti F, Veltman J, Reid JF, Minardi S, et al. : Identification of tumor-specific molecular signatures in intracranial ependymoma and association with clinical characteristics. J Clin Oncol 24 : 5223-5233, 2006 https://doi.org/10.1200/JCO.2006.06.3701
  25. Monoranu CM, Huang B, Zangen IL, Rutkowski S, Vince GH, Gerber NU, et al. : Correlation between 6q25.3 deletion status and survival in pediatric intracranial ependymomas. Cancer Genet Cytogenet 182 : 18-26, 2008 https://doi.org/10.1016/j.cancergencyto.2007.12.008
  26. Olsen TK, Gorunova L, Meling TR, Micci F, Scheie D, Due-Tonnessen B, et al. : Genomic characterization of ependymomas reveals 6q loss as the most common aberration. Oncol Rep 32 : 483-490, 2014 https://doi.org/10.3892/or.2014.3271
  27. Pajtler KW, Witt H, Sill M, Jones DT, Hovestadt V, Kratochwil F, et al. : Molecular classification of ependymal tumors across all CNS compartments, histopathological grades, and age groups. Cancer Cell 27 : 728-743, 2015 https://doi.org/10.1016/j.ccell.2015.04.002
  28. Parker M, Mohankumar KM, Punchihewa C, Weinlich R, Dalton JD, Li Y, et al. : C11orf95-RELA fusions drive oncogenic NF-${\kappa}B$ signalling in ependymoma. Nature 506 : 451-455, 2014 https://doi.org/10.1038/nature13109
  29. Puget S, Grill J, Valent A, Bieche I, Dantas-Barbosa C, Kauffmann A, et al. : Candidate genes on chromosome 9q33-34 involved in the progression of childhood ependymomas. J Clin Oncol 27 : 1884-1892, 2009 https://doi.org/10.1200/JCO.2007.15.4195
  30. Rajaram V, Gutmann DH, Prasad SK, Mansur DB, Perry A : Alterations of protein 4.1 family members in ependymomas : a study of 84 cases. Mod Pathol 18 : 991-997, 2005 https://doi.org/10.1038/modpathol.3800390
  31. Rajaram V, Leuthardt EC, Singh PK, Ojemann JG, Brat DJ, Prayson RA, et al. : 9p21 and 13q14 dosages in ependymomas. A clinicopathologic study of 101 cases. Mod Pathol 17 : 9-14, 2004 https://doi.org/10.1038/modpathol.3800029
  32. Reardon DA, Akabani G, Coleman RE, Friedman AH, Friedman HS, Herndon JE 2nd, et al. : Salvage radioimmunotherapy with murine iodine-131-labeled antitenascin monoclonal antibody 81C6 for patients with recurrent primary and metastatic malignant brain tumors : phase II study results. J Clin Oncol 24 : 115-122, 2006 https://doi.org/10.1200/JCO.2005.03.4082
  33. Rogers HA, Kilday JP, Mayne C, Ward J, Adamowicz-Brice M, Schwalbe EC, et al. : Supratentorial and spinal pediatric ependymomas display a hypermethylated phenotype which includes the loss of tumor suppressor genes involved in the control of cell growth and death. Acta Neuropathol 123 : 711-725, 2012 https://doi.org/10.1007/s00401-011-0904-1
  34. Rubio MP, Correa KM, Ramesh V, MacCollin MM, Jacoby LB, von Deimling A, et al. : Analysis of the neurofibromatosis 2 gene in human ependymomas and astrocytomas. Cancer Res 54 : 45-47, 1994
  35. Scheil S, Bruderlein S, Eicker M, Herms J, Herold-Mende C, Steiner HH, et al. : Low frequency of chromosomal imbalances in anaplastic ependymomas as detected by comparative genomic hybridization. Brain Pathol 11 : 133-143, 2001
  36. Schneider D, Monoranu CM, Huang B, Rutkowski S, Gerber NU, Krauss J, et al. : Pediatric supratentorial ependymomas show more frequent deletions on chromosome 9 than infratentorial ependymomas : a microsatellite analysis. Cancer Genet Cytogenet 191 : 90-96, 2009 https://doi.org/10.1016/j.cancergencyto.2009.02.010
  37. Sherr CJ : The INK4a/ARF network in tumour suppression. Rev Mol Cell Biol 2 : 731-737, 2001 https://doi.org/10.1038/35096061
  38. Singh PK, Gutmann DH, Fuller CE, Newsham IF, Perry A : Differential involvement of protein 4.1 family members DAL-1 and NF2 in intracranial and intraspinal ependymomas. Mod Pathol 15 : 526-531, 2002 https://doi.org/10.1038/modpathol.3880558
  39. Suzuki SO, Iwaki T : Amplification and overexpression of mdm2 gene in ependymomas. Mod Pathol 13 : 548-553, 2000 https://doi.org/10.1038/modpathol.3880095
  40. Taylor MD, Poppleton H, Fuller C, Su X, Liu Y, Jensen P, et al. : Radial glia cells are candidate stem cells of ependymoma. Cancer Cell 8 : 323-335, 2005 https://doi.org/10.1016/j.ccr.2005.09.001
  41. Teo C, Nakaji P, Symons P, Tobias V, Cohn R, Smee R : Ependymoma. Childs Nerv Syst 19 : 270-285, 2003 https://doi.org/10.1007/s00381-003-0753-x
  42. Vera-Bolanos E, Aldape K, Yuan Y, Wu J, Wani K, Necesito-Reyes MJ, et al. : Clinical course and progression-free survival of adult intracranial and spinal ependymoma patients. Neuro Oncol 17 : 440-447, 2015 https://doi.org/10.1093/neuonc/nou162
  43. von Haken MS, White EC, Daneshvar-Shyesther L, Sih S, Choi E, Kalra R, et al. : Molecular genetic analysis of chromosome arm 17p and chromosome arm 22q DNA sequences in sporadic pediatric ependymomas. Genes Chromosomes Cancer 17 : 37-44, 1996 https://doi.org/10.1002/(SICI)1098-2264(199609)17:1<37::AID-GCC6>3.0.CO;2-3
  44. Waha A, Koch A, Hartmann W, Mack H, Schramm J, Sorensen N, et al. : Analysis of HIC-1 methylation and transcription in human ependymomas. Int J Cancer 110 : 542-549, 2004 https://doi.org/10.1002/ijc.20165
  45. Wang Z, Zhang J, Ye M, Zhu M, Zhang B, Roy M, et al. : Tumor suppressor role of protein 4.1B/DAL-1. Cell Mol Life Sci 71 : 4815-4830, 2014 https://doi.org/10.1007/s00018-014-1707-z
  46. Wani K, Armstrong TS, Vera-Bolanos E, Raghunathan A, Ellison D, Gilbertson R, et al. : A prognostic gene expression signature in infratentorial ependymoma. Acta Neuropathol 123 : 727-738, 2012 https://doi.org/10.1007/s00401-012-0941-4
  47. Ward S, Harding B, Wilkins P, Harkness W, Hayward R, Darling JL, et al. : Gain of 1q and loss of 22 are the most common changes detected by comparative genomic hybridisation in paediatric ependymoma. Genes Chromosomes Cancer 32 : 59-66, 2001 https://doi.org/10.1002/gcc.1167
  48. Witt H, Mack SC, Ryzhova M, Bender S, Sill M, Isserlin R, et al. : Delineation of two clinically and molecularly distinct subgroups of posterior fossa ependymoma. Cancer Cell 20 : 143-157, 2011 https://doi.org/10.1016/j.ccr.2011.07.007
  49. Yang I, Nagasawa DT, Kim W, Spasic M, Trang A, Lu DC, et al. : Chromosomal anomalies and prognostic markers for intracranial and spinal ependymomas. J Clin Neurosci 19 : 779-785, 2012 https://doi.org/10.1016/j.jocn.2011.11.004
  50. Zadnik PL, Gokaslan ZL, Burger PC, Bettegowda C : Spinal cord tumours : advances in genetics and their implications for treatment. Nat Rev Neurol 9 : 257-266, 2013
  51. Zheng PP, Pang JC, Hui AB, Ng HK : Comparative genomic hybridization detects losses of chromosomes 22 and 16 as the most common recurrent genetic alterations in primary ependymomas. Cancer Genet Cytogenet 122 : 18-25, 2000 https://doi.org/10.1016/S0165-4608(00)00265-X
  52. Zhou XP, Li YJ, Hoang-Xuan K, Laurent-Puig P, Mokhtari K, Longy M, et al. : Mutational analysis of the PTEN gene in gliomas : molecular and pathological correlations. Int J Cancer 84 : 150-154, 1999 https://doi.org/10.1002/(SICI)1097-0215(19990420)84:2<150::AID-IJC10>3.0.CO;2-#

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