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Open Access 01-12-2016 | Research

Chromosome 1q gain and tenascin-C expression are candidate markers to define different risk groups in pediatric posterior fossa ependymoma

Authors: Asuka Araki, Monika Chocholous, Johannes Gojo, Christian Dorfer, Thomas Czech, Harald Heinzl, Karin Dieckmann, Inge M. Ambros, Peter F. Ambros, Irene Slavc, Christine Haberler

Published in: Acta Neuropathologica Communications | Issue 1/2016

Abstract

Intracranial classic (WHO grade II) and anaplastic (WHO grade III) ependymomas are among the most common tumors in pediatric patients and have due to frequent recurrences and late relapses a relatively poor outcome. The impact of histopathological grading on patient outcome is controversial and therefore, molecular prognostic and predictive markers are needed to improve patient outcome. To date, the most promising candidate marker is chromosome 1q gain, which has been associated in independent studies with adverse outcome. Furthermore, gene expression and methylation profiles revealed distinct molecular subgroups in the supratentorial and posterior fossa (PF) compartment and Laminin alpha-2 (LAMA2) and Neural Epidermal Growth Factor Like-2 (NELL2) were suggested as surrogate markers for the two PF subgroups PF-EPN-A and PF-EPN-B. PF-EPN-A tumors were also characterized by tenascin-C (TNC) expression and tenascin-C has been suggested as candidate gene on 9q, involved in tumor progression. Therefore, we have analyzed the status of chromosome 1q, TNC, LAMA2, and NELL2 expression in a series of pediatric PF ependymomas in terms of their frequency, associations among themselves, and clinical parameters, as well as their prognostic impact. We confirm the negative prognostic impact of 1q gain and TNC expression and could classify PF ependymomas by these two markers into three molecular subgroups. Tumors with combined 1q gain and TNC expression had the poorest, tumors without 1q gain and TNC expression had a favorable and TNC positive 1q non-gained cases had an intermediate outcome. We found also differences in age and tumor grade in the three subgroups and thus, provide evidence that PF pediatric ependymomas can be divided by chromosome 1q status and TNC expression in three molecular subgroups with distinct clinico-pathological features. These analyses require only few amounts of tumor tissue, are broadly available in the routine clinical neuropathological setting and thus, could be used in further therapy trials to optimize treatment of ependymoma patients.

Taylor MD, Poppleton H, Guha A, Gajjar A, Gilbertson RJ. Radial glia cells are candidate stem cells of ependymoma. Cancer Cell. 2005;8:323–35. doi:10.1016/j.ccr.2005.09.001.CrossRefPubMed

McGuire CS, Sainani KL, Fisher PG. Incidence patterns for ependymoma: a Surveillance, Epidemiology, and End Results study. J Neurosurg. 2009;110:725–9. doi:10.3171/2008.9.JNS08117.CrossRefPubMed

Ostrom QT, de Blank PM, Kruchko C, Petersen CM, Liao P, Finlay JL, Stearns DS, Wolff JE, Wolinsky Y, Letterio JJ, Barnholtz-Sloan JS. Alex’s Lemonade Stand Foundation Infant and Childhood Primary Brain and Central Nervous System Tumors Diagnosed in the United States in 2007-2011. Neuro Oncol. 2015;16 Suppl 10:x1–x36. doi:10.1093/neuonc/nou327.CrossRefPubMed

Grundy RG, Wilne SA, Weston CL, Robinson K, Lashford LS, Ironside J, Cox T, Chong WK, Campbell RH, Bailey CC, Gattamaneni R, Picton S, Thorpe N, Mallucci C, English MW, Punt JA, Walker DA, Ellison DW, Machin D. Primary postoperative chemotherapy without radiotherapy for intracranial ependymoma in children: the UKCCSG/SIOP prospective study. Lancet Oncol. 2007;8:696–705. doi:10.1016/S1470–2045(07)70208–5.CrossRefPubMed

Massimino M, Gandola L, Giangaspero F, Sandri A, Valagussa P, Perilongo G, Garre M-L, Ricardi U, Forni M, Genitori L, Scarzello G, Spreafico F, Barra S, Mascarin M, Pollo B, Gardiman M, Cama A, Navarria P, Brisigotti M, Collini P, Balter R, Fidani P, Stefanelli M, Burnelli R, Potepan P, Podda M, Sotti G, Madon E. Hyperfractionated radiotherapy and chemotherapy for childhood ependymoma: final results of the first prospective AIEOP (Associazione Italiana di Ematologia-Oncologia Pediatrica) study. Int J Radiat Oncol Biol Phys. 2004;58:1336–45. doi:10.1016/j.ijrobp.2003.08.030.CrossRefPubMed

Merchant TE, Li C, Xiong X, Kun LE, Boop FA, Sanford RA. Conformal radiotherapy after surgery for paediatric ependymoma: a prospective study. Lancet Oncol. 2009;10:258–66. doi:10.1016/S1470-2045(08)70342-5.CrossRefPubMedPubMedCentral

Pejavar S, Polley M-Y, Rosenberg-Wohl S, Chennupati S, Prados MD, Berger MS, Banerjee A, Gupta N, Haas-Kogan D. Pediatric intracranial ependymoma: the roles of surgery, radiation and chemotherapy. J Neurooncol. 2011;106:367–75. doi:10.1007/s11060-011-0671-9.CrossRefPubMed

Cage TA, Clark AJ, Aranda D, Gupta N, Sun PP, Parsa AT, Auguste KI. A systematic review of treatment outcomes in pediatric patients with intracranial ependymomas. J Neurosurg Pediatr. 2013;11:673–81. doi:10.3171/2013.2.PEDS12345.CrossRefPubMed

Amirian ES, Armstrong TS, Aldape KD, Gilbert MR, Scheurer ME. Predictors of survival among pediatric and adult ependymoma cases: a study using Surveillance, Epidemiology, and End Results data from 1973 to 2007. Neuroepidemiology. 2012;39:116–24. doi:10.1159/000339320.CrossRefPubMedPubMedCentral

10.

Tihan T, Zhou T, Holmes E, Burger PC, Ozuysal S, Rushing EJ. The prognostic value of histological grading of posterior fossa ependymomas in children: a Children’s Oncology Group study and a review of prognostic factors. Mod Pathol. 2008;21:165–77. doi:10.1038/modpathol.3800999.PubMed

11.

Louis DN, Perry A, Reifenberger G, Deimling A, Figarella-Branger D, Cavenee WK, Ohgaki H, Wiestler OD, Kleihues P, Ellison DW. The 2016 World Health Organization Classification of Tumors of the Central Nervous System: a summary. Acta Neuropathol. 2016:131:803–20. doi:10.1007/s00401-016-1545-1.

12.

Figarella-Branger D, Civatte M, Bouvier-Labit C, Gouvernet J, Gambarelli D, Gentet JC, Lena G, Choux M, Pellissier JF. Prognostic factors in intracranial ependymomas in children. J Neurosurg. 2000;93:605–13. doi:10.3171/jns.2000.93.4.0605.CrossRefPubMed

13.

Modena P, Buttarelli FR, Miceli R, Piccinin E, Baldi C, Antonelli M, Morra I, Lauriola L, Di Rocco C, Garre ML, Sardi I, Genitori L, Maestro R, Gandola L, Facchinetti F, Collini P, Sozzi G, Giangaspero F, Massimino M. Predictors of outcome in an AIEOP series of childhood ependymomas: a multifactorial analysis. Neuro Oncol. 2012;14:1346–56. doi:10.1093/neuonc/nos245.CrossRefPubMedPubMedCentral

14.

Raghunathan A, Wani K, Armstrong TS, Vera-Bolanos E, Fouladi M, Gilbertson R, Gajjar A, Goldman S, Lehman NL, Metellus P, Mikkelsen T, Necesito-Reyes MJT, Omuro A, Packer RJ, Partap S, Pollack IF, Prados MD, Robins HI, Soffietti R, Wu J, Miller CR, Gilbert MR, Aldape KD, Network CER. Histological predictors of outcome in ependymoma are dependent on anatomic site within the central nervous system. Brain Pathol. 2013;23:584–94. doi:10.1111/bpa.12050.CrossRefPubMed

15.

Ellison DW, Kocak M, Figarella-Branger D, Felice G, Catherine G, Pietsch T, Frappaz D, Massimino M, Grill J, Boyett JM, Grundy RG. Histopathological grading of pediatric ependymoma: reproducibility and clinical relevance in European trial cohorts. J Negat Results Biomed. 2011;10:7. doi:10.1186/1477–5751–10–7.CrossRefPubMedPubMedCentral

16.

Li AM, Dunham C, Tabori U, Carret A-S, McNeely PD, Johnston D, Lafay-Cousin L, Wilson B, Eisenstat DD, Jabado N, Zelcer S, Silva M, Scheinemann K, Fryer C, Hendson G, Fotovati A, Hawkins C, Yip S, Dunn SE, Hukin J. EZH2 expression is a prognostic factor in childhood intracranial ependymoma: A Canadian Pediatric Brain Tumor Consortium study. Cancer. 2015. doi:10.1002/cncr.29198.

17.

Mendrzyk F. Identification of Gains on 1q and Epidermal Growth Factor Receptor Overexpression as Independent Prognostic Markers in Intracranial Ependymoma. Clin Cancer Res. 2006;12:2070–9. doi:10.1158/1078-0432.CCR-05-2363.CrossRefPubMed

18.

Puget S, Grill J, Valent A, Bieche I, Dantas-Barbosa C, Kauffmann A, Dessen P, Lacroix L, Geoerger B, Job B, Dirven C, Varlet P, Peyre M, Dirks PB, Sainte-Rose C, Vassal G. Candidate genes on chromosome 9q33-34 involved in the progression of childhood ependymomas. J Clin Oncol. 2009;27:1884–92. doi:10.1200/JCO.2007.15.4195.CrossRefPubMed

19.

Ridley L, Rahman R, Brundler M-A, Ellison D, Lowe J, Robson K, Prebble E, Luckett I, Gilbertson RJ, Parkes S, Rand V, Coyle B, Grundy RG, Children’s Cancer and Leukaemia Group Biological Studies Committee. Multifactorial analysis of predictors of outcome in pediatric intracranial ependymoma. Neuro Oncol. 2008;10:675–89. doi:10.1215/15228517-2008-036.CrossRef

20.

Tabori U, Wong V, Ma J, Shago M, Alon N, Rutka J, Bouffet E, Bartels U, Malkin D, Hawkins C. Telomere maintenance and dysfunction predict recurrence in paediatric ependymoma. Br J Cancer. 2008;99:1129–35. doi:10.1038/sj.bjc.6604652.CrossRefPubMedPubMedCentral

21.

Wolfsberger S, Fischer I, Höftberger R, Birner P, Slavc I, Dieckmann K, Czech T, Budka H, Hainfellner J. Ki-67 immunolabeling index is an accurate predictor of outcome in patients with intracranial ependymoma. Am J Surg Pathol. 2004;28:914–20.CrossRefPubMed

22.

Kilday JP, Rahman R, Dyer S, Ridley L, Lowe J, Coyle B, Grundy R. Pediatric Ependymoma: Biological Perspectives. Mol Cancer Res. 2009;7:765–86. doi:10.1158/1541–7786.MCR–08–0584.CrossRefPubMed

23.

Carter M, Nicholson J, Ross F, Crolla J, Allibone R, Balaji V, Perry R, Walker D, Gilbertson R, Ellison DW. Genetic abnormalities detected in ependymomas by comparative genomic hybridisation. Br J Cancer. 2002;86:929–39. doi:10.1038/sj.bjc.6600180.CrossRefPubMedPubMedCentral

24.

Godfraind C, Kaczmarska JM, Kocak M, Wright KD, Sanford RA, Boop FA, Gajjar A, Merchant TE, Ellison DW. Distinct disease-risk groups in pediatric supratentorial and posterior fossa ependymomas. Acta Neuropathol. 2012;124:247–57. doi:10.1007/s00401–012–0981–9.CrossRefPubMedPubMedCentral

25.

Kilday JP, Lowe J, Ellison DW, Gilbertson RJ, Coyle B, Grundy RG. Copy Number Gain of 1q25 Predicts Poor Progression-Free Survival for Pediatric Intracranial Ependymomas and Enables Patient Risk Stratification: A Prospective European Clinical Trial Cohort Analysis on Behalf of the Children“s Cancer Leukaemia Group (CCLG), Societe Francaise d”Oncologie Pediatrique (SFOP), and International Society for Pediatric Oncology (SIOP). Clin Cancer Res. 2012;18:2001–11. doi:10.1158/1078–0432.CCR–11–2489.CrossRefPubMed

26.

Korshunov A, Witt H, Remke M, Ryzhova M, Milde T, Bender S, Kulozik AE, Witt O, von Deimling A, Lichter P. Molecular Staging of Intracranial Ependymoma in Children and Adults. J Clin Oncol. 2010;28:3182–90. doi:10.1200/JCO.2009.27.3359.CrossRefPubMed

27.

Pajtler KW, Witt H, Sill M, Jones DTW, Hovestadt V, Kratochwil F, Wani K, Tatevossian R, Punchihewa C, Johann P, Reimand J, Warnatz H-J, Ryzhova M, Mack S, Ramaswamy V, Capper D, Schweizer L, Sieber L, Wittmann A, Huang Z, van Sluis P, Volckmann R, Koster J, Versteeg R, Fults D, Toledano H, Toledano H, Avigad S, Hoffman LM, Hoffman LM, Donson AM, Foreman N, Hewer E, Zitterbart K, Gilbert M, Armstrong TS, Gupta N, Allen JC, Karajannis MA, Zagzag D, Hasselblatt M, Kulozik AE, Witt O, Collins VP, von Hoff K, Rutkowski S, Pietsch T, Bader G, Yaspo M-L, von Deimling A, Lichter P, Taylor MD, Gilbertson R, Ellison DW, Ellison DW, Aldape K, Korshunov A, Kool M, Pfister SM. Molecular Classification of Ependymal Tumors across All CNS Compartments, Histopathological Grades, and Age Groups. Cancer Cell. 2015;27:728–43. doi:10.1016/j.ccell.2015.04.002.CrossRefPubMedPubMedCentral

28.

Witt H, Mack SC, Ryzhova M, Bender S, Sill M, Isserlin R, Benner A, Hielscher T, Milde T, Remke M, Jones DTW, Northcott PA, Garzia L, Bertrand KC, Wittmann A, Yao Y, Roberts SS, Massimi L, Van Meter T, Weiss WA, Gupta N, Grajkowska W, Lach B, Cho Y-J, Deimling Von A, Kulozik AE, Witt O, Bader GD, Hawkins CE, Tabori U, Guha A, Rutka JT, Lichter P, Korshunov A, Taylor MD, Pfister SM. Delineation of Two Clinicallyand Molecularly Distinct Subgroups of Posterior Fossa Ependymoma. Cancer Cell. 2011;20:143–57. doi:10.1016/j.ccr.2011.07.007.CrossRefPubMedPubMedCentral

29.

Parker M, Mohankumar KM, Punchihewa C, Weinlich R, Dalton JD, Li Y, Lee R, Tatevossian RG, Phoenix TN, Thiruvenkatam R, White E, Tang B, Orisme W, Gupta K, Rusch M, Chen X, Li Y, Nagahawhatte P, Hedlund E, Finkelstein D, Wu G, Shurtleff S, Easton J, Boggs K, Yergeau D, Vadodaria B, Mulder HL, Becksford J, Gupta P, Huether R, Ma J, Song G, Gajjar A, Merchant T, Boop F, Smith AA, Ding L, Lu C, Ochoa K, Zhao D, Fulton RS, Fulton LL, Mardis ER, Wilson RK, Downing JR, Green DR, Zhang J, Ellison DW, Gilbertson RJ. C11orf95–RELA fusions drive oncogenic NF-kB signalling in ependymoma. Nature. 2014;506:451–5. doi:10.1038/nature13109.CrossRefPubMedPubMedCentral

30.

Pietsch T, Wohlers I, Goschzik T, Dreschmann V, Denkhaus D, Dörner E, Rahmann S, Klein‐Hitpass L. Supratentorial ependymomas of childhood carry C11orf95-RELA fusions leading to pathological activation of the NF-kB signaling pathway. Acta Neuropathol. 2014;127:609–11. doi:10.1007/s00401-014-1264-4.CrossRefPubMed

31.

Korshunov A, Golanov A, Timirgaz V. Immunohistochemical markers for prognosis of ependymal neoplasms. J Neurooncol. 2002;58:255–70.CrossRefPubMed

32.

Woehrer A, Sander P, Haberler C, Kern S, Maier H, Preusser M, Hartmann C, Kros JM, Hainfellner JA, Research Committee of the European Confederation of Neuropathological Societies. FISH-based detection of 1p 19q codeletion in oligodendroglial tumors: procedures and protocols for neuropathological practice - a publication under the auspices of the Research Committee of the European Confederation of Neuropathological Societies (Euro-CNS). Clin Neuropathol. 2011;30:47–55. doi:10.5414/NPP30047.CrossRef

33.

Bogen D, Brunner C, Walder D, Ziegler A, Abbasi R, Ladenstein RL, Noguera R, Martinsson T, Amann G, Schilling FH, Ussowicz M, Benesch M, Ambros PF, Ambros IM. The genetic tumor background is an important determinant for heterogeneous MYCN-amplified neuroblastoma. Int J Cancer. 2016;139:153–63. doi:10.1002/ijc.30050.CrossRefPubMedPubMedCentral

34.

Firth D. Bias reduction of maximum likelihood estimates. Biometrika. 1993;80:27–38. doi:10.1093/biomet/80.1.27.CrossRef

35.

Dyer S, Prebble E, Davison V, Davies P, Ramani P, Ellison D. Genomic imbalances in pediatric intracranial ependymomas define clinically relevant groups. Am J Pathol. 2002;161:2133–41. doi:10.1016/S0002-9440(10)64491–4.CrossRefPubMedPubMedCentral

36.

Hirose Y, Aldape K, Bollen A, James CD, Brat D, Lamborn K, Berger M, Feuerstein BG. Chromosomal abnormalities subdivide ependymal tumors into clinically relevant groups. Am J Pathol. 2001;158:1137–43. doi:10.1016/S0002–9440(10)64061–8.CrossRefPubMedPubMedCentral

37.

Rajeshwari M, Sharma MC, Kakkar A, Nambirajan A, Suri V, Sarkar C, Singh M, Saran RK, Gupta RK. Evaluation of chromosome 1q gain in intracranial ependymomas. J Neurooncol. 2016:127:271–8. doi:10.1007/s11060-015-2047-z.

38.

Ward S, Harding B, Wilkins P, Harkness W, Hayward R, Darling JL, Thomas DG, Warr T. Gain of 1q and loss of 22 are the most common changes detected by comparative genomic hybridisation in paediatric ependymoma. Genes Chromosomes Cancer. 2001;32:59–66. doi:10.1002/gcc.1167.CrossRefPubMed

39.

Rand V, Prebble E, Ridley L, Howard M, Wei W, Brundler M-A, Fee BE, Riggins GJ, Coyle B, Grundy RG. Investigation of chromosome 1q reveals differential expression of members of the S100 family in clinical subgroups of intracranial paediatric ependymoma. Br J Cancer. 2008;99:1136–43. doi:10.1038/sj.bjc.6604651.CrossRefPubMedPubMedCentral

40.

Garwood J, Garcion E, Dobbertin A, Heck N, Calco V, Ffrench-Constant C, Faissner A. The extracellular matrix glycoprotein Tenascin-C is expressed by oligodendrocyte precursor cells and required for the regulation of maturation rate, survival and responsiveness to platelet-derived growth factor. Eur J Neurosci. 2004;20:2524–40. doi:10.1111/j.1460–9568.2004.03727.x.CrossRefPubMed

41.

Garcion E, Halilagic A, Faissner A, Ffrench-Constant C. Generation of an environmental niche for neural stem cell development by the extracellular matrix molecule tenascin C. 2004. p. 131:3423–3432. doi:10.1242/dev.01202.

42.

Herold-Mende C, Mueller MM, Bonsanto MM, Schmitt HP, Kunze S, Steiner HH. Clinical impact and functional aspects of tenascin-C expression during glioma progression. Int J Cancer. 2002;98:362–9. doi:10.1002/ijc.10233.CrossRefPubMed

43.

Venning FA, Wullkopf L, Erler JT. Targeting ECM Disrupts Cancer Progression. Frontiers Oncology. 2015;5:1377–15. doi:10.3389/fonc.2015.00224.CrossRef

44.

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. 2013. doi:10.1007/s11060–013–1287–z.

45.

Korshunov A, Golanov A, Timirgaz V. Immunohistochemical markers for intracranial ependymoma recurrence - An analysis of 88 cases. J Neurol Sci. 2000;177:72–82.CrossRefPubMed

46.

Zámecník J, Chánová M, Tichý M, Kodet R. Distribution of the extracellular matrix glycoproteins in ependymomas - an immunohistochemical study with follow-up analysis. Neoplasma. 2004;51:214–22.PubMed

47.

Modena P, Facchinetti F, Giangaspero F, Genitori L, Massimino M, Sozzi G. Identification of Tumor-Specific Molecular Signatures in Intracranial Ependymoma and Association With Clinical Characteristics. J Clin Oncol. 2006;24:5223–33. doi:10.1200/JCO.2006.06.3701.CrossRefPubMed

Title: Chromosome 1q gain and tenascin-C expression are candidate markers to define different risk groups in pediatric posterior fossa ependymoma
Authors: Asuka Araki
Monika Chocholous
Johannes Gojo
Christian Dorfer
Thomas Czech
Harald Heinzl
Karin Dieckmann
Inge M. Ambros
Peter F. Ambros
Irene Slavc
Christine Haberler
Publication date: 01-12-2016
Publisher: BioMed Central
Published in: Acta Neuropathologica Communications / Issue 1/2016
Electronic ISSN: 2051-5960
DOI: https://doi.org/10.1186/s40478-016-0349-9

At a glance: The STEP trials

Springer Medicine

Chromosome 1q gain and tenascin-C expression are candidate markers to define different risk groups in pediatric posterior fossa ependymoma

Abstract

At a glance: The STEP trials

Springer Medicine

Abstract

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