MEDICINE

Molecular Characteristics of Pediatric Ependymomas:A Systematic Review

Monserrat Pérez-Ramírez1 & Teresa Juárez-Cedillo2& Antonio García-Méndez3 & Normand García-Hernández1

Accepted: 5 September 2019# Springer Nature Switzerland AG 2019

AbstractThe prognosis for patients diagnosed with ependymoma is relatively poor, with a 5-year overall survival rate of 24–75%. Currently, tumors are treated by surgical resection followed by radiotherapy, as resection is the most consistentprognostic marker (up to 80%). Therefore, there is a pressing need to improve our understanding of the biology ofthese tumors and to develop new therapeutic targets. The present work was a systematic review of the currentmolecular knowledge of pediatric ependymomas. From January 2000 to December 2017, we carried out a searchusing BMeSH^ (Medical Subject Heading), and Bfree-text^ protocols in the databases Medline/PubMed, SCOPUS,Web of Science, and EMBASE (OVID platform), combining the terms chromosomal alterations, genetic changes,epigenetic changes, and protein expression changes. We selected articles with samples from pediatric patients andchose publications with complete clinical features. Only 33 articles met the criteria for a meta-analysis, suggested bythe state of methylation and expression of a characteristic marker of pediatric ependymomas. We found a chromo-somal alteration and one gene associated with survival; these are candidates for bad prognosis biomarkers.

Keywords Ependymoma .Molecular characteristic . Systematic review . Pediatric patients

Introduction

Ependymoma (EP) arises from the ependymal cells of thefourth cerebral ventricle and the spinal cord. These tumorscan develop in both adult and children patients; however,

intracranial EP occurs more frequently in children, whereasspinal EPs are more frequent in adults. These tumors are clas-sified by their location as infra and supratentorial EPs [1].

EP is the third most common pediatric tumor of the centralnervous system and the prognosis is relatively poor for pa-tients with this diagnosis, with a 5-year overall survival rateof 24–75%; therefore, EPs are considered a public healthproblem. These tumors are treated with surgical resectionfollowed by radio- and chemotherapy. Actually, resection isthe best prognostic marker (up to 80%) used for clinical diag-nostic; therefore, it is necessary to understand the tumorigen-esis of EP in order to develop new therapeutic targets [2, 3].

The clinical features of EPs used for prognosis—such as pa-tient age, tumor location, extent of surgical resection, and tumorhistopathology grade—are insufficient and have inconsistent re-sults, so it is necessary to come up with strategies to improvetreatment and provide an exact prognosis [4, 5]. Several studieshave suggested that epigenetic silencing of tumor suppressorgenes and expression changes are an important mechanisms ofEP pathogenesis in supratentorial and spinal tumors [2].

In this systematic review, we aimed to determine the mo-lecular characteristics of these tumors that may establishtumor markers.

This article is part of the Topical Collection on Medicine

* Normand García-Hernándeznormandgarcia@gmail.com

1 Unidad de Investigación Médica en Genética Humana, Hospital dePediatría BDr. Silvestre Frenk Freud,^ CentroMédico Nacional SigloXXI, Instituto Mexicano del Seguro Social, Av. Cuauhtémoc 330,Col. Doctores, Del. Cuauhtémoc, 06720 Ciudad de México, Mexico

2 Unidad de Investigación Epidemiológica y en Servicios de Salud,Área Envejecimiento, CNM Siglo XXI, IMSS, ActualmenteComisionada en Unidad de Investigación en Epidemiología Clínica,Hospital Regional núm. 1 Dr. Carlos MacGregor Sánchez Navarro,IMSS, Colonia Del Valle, Delegación, Benito Juárez, 03100 Ciudadde México, Mexico

3 Neurocirugía Pediátrica, Hospital General BDr. Gaudencio GonzálezGarza,^ Centro Médico Nacional BLa Raza^, Instituto Mexicano delSeguro Social, Calzada Vallejo y Jacarandas S/N, Col. La Raza, Del.Azcapotzalco, 02980 Ciudad de México, Mexico

https://doi.org/10.1007/s42399-019-00147-5SN Comprehensive Clinical Medicine (2019) 1:861–868

/Published online: 24 October 2019

Methods

Search Strategy and Selection Criteria

An electronic search was carried out in the Medline/PubMedand SCOPUS, Web of Science, and Ovid/EMBASE databasesand was restricted to articles published in English betweenJanuary 2000 and December 2017. The intent was to identifychromosomal alterations and changes in the methylation statusand gene expression that are part of the molecular characteristicsof pediatric EP and that could be use as molecular prognosticbiomarkers. These studies were examined based on their title,abstract, and keywords. The strategy used a combination of thefollowing key terms: BEpendymoma pediatric^; BEpendymomachildren^; BEpendymoma molecular^; BBrain tumor molecularependymoma^; BEpendymoma biomarker^ (Fig. 1). We alsoexamined the references in the selected articles, looking forstudies that were not selected in the initial query.

Included articles were based on an a priori selected set ofcriteria: articles published in English, complete data of patients,complete text, cross-sectional studies, molecular data studies, andstudies carried out totally or partially in pediatric patients (under18 years of age). If the reviewed articles were based on pediatricand adult patients, it was considered that the samples would beeasily identified through the codes or numbering that differentauthors granted for each of the samples. The patients had com-plete clinical characteristics that included age, sex, and diagnosis;in addition, the results described were specific for each sample.

The primary outcomewas data on changes in chromosomalalterations, methylation status, gene and protein expressionreported in pediatric patients, cross-sectional studies, molecu-lar changes associated with the patient’s prognosis, frequencyof appearance of molecular changes, and values of hazardratios and odds ratios.

The exclusion criteria included case-controlled studies,studies without measures of association, and case series. Nosystematic reviews or meta-analyses on this topic were found.

Data Extraction

Three reviewers participated in the review process. Two re-viewers completed the initial review, examined the papers,confirmed the inclusion and exclusion criteria, and completedthe second stage, extracting all data; a third reviewer indepen-dently examined the data to identify any discrepancies be-tween reviewers. Discrepancies in article selection were re-solved by discussion among the reviewers. A similar approachwas used to determine which of these studies should be in-cluded in the meta-analysis. Information about date of publi-cation, country where the study was undertaken, sample size,data relating to participants, a specific illness, age, sex, histo-pathology diagnosis, and tumor location was acquired fromthe included articles for full review. Odds ratios (ORs), andrate ratios (RRs), with 95% confidence interval (CI) for eachchromosomal alteration, genetic, epigenetic, and protein ex-pression were extracted when they were available.

Statistical Analysis

Thirty-three studies were selected and included for this sys-tematic review. The number of studies, analyzed by condition,varied from two to five. For each study and each characteris-tic, an event rate and its CI were computed from the reportednumbers, considering the reference group. Review Manager5.3 was used for the analyses [Review Manager (RevMan)[computer program]. Version 5.3. Copenhagen: The NordicCochrane Centre, The Cochrane Collaboration, 2014].Random-effects models were conducted, separating the stud-ies into one analysis for those reporting OR statistics andanother for those reporting OR. Heterogeneity was estimatedusing the I2 statistic [6]. The I2 describes the percentage ofvariation across studies due to heterogeneity rather thanchance alone [6, 7]. As the I2 percentage increases, so too doesthe proportion of effect size variability that is due to between-study heterogeneity.

In order to calculate bias, the tests described by Begg et al.and Egger et al. [8, 9] were used. Funnel plots were generatedwith a confidence interval of 95%, according to the random-effects meta-analysis proposed by DerSimonian and Laird[10]; Tau2 adjusts the standard error and the effects of theintervention of the studies included in the meta-analysis.Finally, the frequency of chromosomal, genetic, and epigenet-ic alterations was analyzed.

Results

Article Selection

Initially, we identified 3564 related articles. After evaluation,33 studies fulfilled the inclusion criteria as follows: 14Fig. 1 Flow diagram of process for identification of relevant studies

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contained studies on chromosomal alterations, 5 had methyl-ation data, 4 articles contained information related to the ex-pression of messenger RNA, and 13 referred to proteins.Table 1 shows the studies included in the analysis with samplesize, study design, and the alteration detected in the moleculeof interest.

Chromosomal Alterations

From the selected articles, 14 were related to chromosomalalterations to the EP. We considered a total of 545 samplesfrom the analyzed publications. According to this analysis, thealterations oscillated up to 2% of the total data (data not

shown). The most frequent chromosomal changes were gainsat 1q, 9q, 9p, and 17q and losses at 1p, 3p, 6q, and 13q. Wefound chromosomal alterations (losses and gains) in severalcytobands. From these data, we found that chromosomes 1q,6q, 9p, 13q, and 22q are features of pediatric ependymal tu-mors (Fig. 2). The alterations showed the following statisticalvalues: to 1q (Tau2 = 1.53, I2 = 45%, P = 0.02, χ2 = 9.13), to9p (Tau2 = 1.27, χ2 = 6.84, I2 = 42%, P = 0.24) to 6q (Tau2 =0.00, χ2 = 2.06, I2 = 0%, P = 0.58), to 13q (Tau2 = 0.00, χ2 =0.08, I2 = 0%, P = 0.14), and to 22q indicated perfect homo-geneity (Tau2 = 0.00, χ2 = 0.08, I2 = 0%, P = 0.14). Over awide range, our model indicated heterogeneity with the fol-lowing statistical values: Tau2 = 1.72, χ2 = 37.8, P = 0.01,

Table 1 Articles included in thesystematic review Reference Methodology Detected alteration N

Suzuki et al. 2000 [11] IHCa Protein 11

Lamszus et al. 2001 [12] PCRb Chromosomal alteration 10

Hirose et al. 2001 [13] CGHc Chromosomal alteration 14

Ward et al. 2001 [14] CGH Chromosomal alteration 36

Dyer et al. 2002 [15] CGH Chromosomal alteration 42

Gilbertson et al. 2002 [16] qRT-PCRd Methylation 16

Jeuken et al. 2002 [17] CGH Chromosomal alteration 5

Singh et al. 2002 [18] IHC Protein 10

Zamecnik et al. 2003 [19] IHC Protein 31

Waha et al. 2004 [20] MS-PCRe Expression 27

Ammerlaan et al. 2005 [1] aCGHf Chromosomal alteration 19

Tabori et al. 2006 [21] qRT-PCR Methylation 65

Karakoula et al. 2008 [22] qRT-PCR Methylation and expression 31

Moronaru et al. 2008 [23] PCR Chromosomal alteration 29

Pezzolo et al. 2008 [24] CGH Chromosomal alteration 18

Rand et al. 2008 [25] aCGH Chromosomal alteration 7

Snuderl et al. 2008 [26] IHC Protein 41

Puget et al. 2009 [27] aCGH Chromosomal alteration 59

Rousseau et al. 2010 [28] aCGH Chromosomal alteration 45

Andreiuolo et al. 2010 [29] IHC Protein 66

Korshunov et al. 2010 [30] aCGH Chromosomal alteration 190

Alexiou et al. 2011 [31] IHC Protein 13

Modena et al. 2012 [5] IHC Protein 47

Hagel et al. 2013 [32] IHC Protein 25

Moreno et al. 2013 [33] IHC Protein 12

Barszczyk et al. 2014 [34] qRT-PCR Expression 97

Gupta et al. 2014 [35] FISHh Chromosomal alteration 19

Virág et al. 2014 [36] IHC Protein 16

Mack et al. 2014 [37] Array Methylation 10

Li et al. 2015 [38] IHC Protein 174

Araki et al. 2016 [39] FISH, IHC Chromosomal alteration, protein 52

Chen et al. 2016 [40] IHC Protein 174

Gojo et al. 2017 [41] qRT-PCR Methylation and expression 24

a Immunochemistry, b polymerase chain reaction, c comparative genomic hybridization, d real-time polymerasechain reaction, emethylation-specific PCR, f array CGH, h fluorescence hybridization in situ

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I2 = 0%. Therefore, chromosomal alterations in 1q, 6q, 9p,13q, and 22q are features of pediatric ependymal tumors.Additionally, HR values were considered.We found that chro-mosome 1q25 at intracranial EP is the best candidate for aprognostic biomarker in pediatric EP, and this chromosomecorrelated with lower progression-free survival and overallsurvival (Fig. 3). Our model was heterogeneous with the

following statistical values: χ2 = 4.76, P = 0.03, I2 = 79%,Tau2 = 2.46. The Funnel plot show symmetric data dispersion.

Methylation Analysis

We assessed five related articles on methylation that included247 patients, in which we found genes with changed

Fig. 2 Forest plot ofchromosomal alterations

Fig. 3 Forest plot ofchromosomal alterations andprognostic

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methylation status in the pediatric EP: hTERT, RAC2, andCHIBBY, with the following frequencies 27.8%, 9.2%, and8.8%, respectively. These results suggested that hypomethy-lation of hTERT is associated with pediatric patients diag-nosed with intracranial EP (Fig. 4a); however, the change inthe methylation status did not correlate with the prognosis.The model indicated homogeneity with the following statisti-cal values: Tau2 = 0.0, χ2 = 0.02, I2 = 0%. The Funnel plotshow symmetric data dispersion.

Gene Expression

We selected four articles that met the eligibility criteria with136 samples. It was observed that genes with the most fre-quent expression changes were hTERT (36%), ERBB (33%),ERBB1 (12%), ERBB2 (12%), ERBB3 (9%), STB (4%), SHC1(6%), and TPR (9%). We observed that hTERT and ERBBgenes are features of pediatric intracranial ependymal tumors,but only hTERT correlated with a bad prognosis for patientswith the following statistical values: Tau2 = 1.21, χ2 = 3.31,P = 0.19, I2 = 40%, which indicated that our model was het-erogeneous (Fig. 4b) The funnel plot shows symmetric datadispersion.

Protein Expression

We selected 14 publications that met the eligibility criteriawith protein expression assays, with a total of 697 patients

showing different states of protein expression. We reviewedthe frequencies of the results, where it was observed thatEGFR was found with 22.02% of the cases, with strong ex-pression, andwith 18.75%with absence of protein expression;for Cav-1 with 12.35% had a strong expression, and 13.54%had weak staining. With respect to YB1, the expression wasweak with a prevalence of 19.94%. EZH2 showed weak ornegative staining with a prevalence of 19.35%. NCL showedstrong staining in 19.94% and weak staining in 10.86% of thecases (data not shown).

Discussion

We found 3564 articles that were related to EP, but most re-ferred to the clinical aspects of this neoplasm and some othersdid not meet the inclusion criteria, such as articles published inEnglish, with complete data of patients, complete text, cross-sectional studies, molecular data studies, and studies carriedout totally or partially in pediatric patients (under 18 years ofage). Therefore, a total of 33 studies related to EP were in-cluded in this work. These papers were related to molecularstudies in EP and included complete data of patients and com-plied with the eligibility criteria. Regarding data analysis, weconsidered the value of OR and HR; heterogeneity was eval-uated with χ2, P value, and I2; the publication biases wereevaluated using the funnel plot and Tau2 values [8–10].

EPs have been classified into subgroups: Posterior FosaGroup A (PFA) and Group B (PFB), each associated with

Fig. 4 (a) Forest plot ofmethylation status. (b) hTERTandprognostic

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distinct transcriptomic, genetic, epigenetic, and clinical fea-tures. Cases of the PFA subgroup were almost exclusivelyfound in young children. The subgroups of supratentorial EPST-YAP1 and ST-RELA are common in children; theC11orf95-RELA fusions are the main drivers of ST-EPN-RELA subgroup tumors [42]. It is important to determine ifother molecular characteristics are involved in tumorigenesisand are candidates for use as prognostic markers.

The following alterations were reported: losses in 1p, 3p11,3p12, 3p23-p13, 3p24, 3q23-qter, 4q33-qter, 18q22.2, 22,gains distributed along chromosomes 7, 12, 15, cytobands6q14–q27, 9q13, 9q21–q32, 9q33, 9q34, 10q25.2–q26.3,10q25.2–q26.3 and 19p13, the loss at 18q22.2. These alter-ations were significantly associated with patients over 3 years[24, 28]; after data analysis and considering biases analysis,we found that the most frequent and characteristic chromo-somal changes of the ependymal tumors were gains at 1q, 9q,and 17q and losses at 1p, 3p, 6q, 13q, and 22q. Furthermore,the regions 6q24.3 and 6q25.2–q25.3 were defined as theregions with the highest number of deletions and could playa role in the pathogenesis and biology of EP [23].

It was determined that the most important chromosomalalterations, such as the chromosome 22 loss, was that foundin 57.5% of the studied EP cases; it was associated with 45%of intracranial EP cases and 82% of spinal EP [1]. This isconsistent with the idea that the loss or mutation of NF2 isfrequently involved in their development, ranging from 30%to 71% of the patients [12, 15, 18]. Another important chro-mosomal alteration is a gain at 1q, which is one of the mostcommon regions with a gain in EP [24, 25]. It has thereforebeen important to investigate the gain at 1q as a potentialmarker of a poor prognosis in pediatric EPs treated in a stan-dard manner [15]. The cytoband 1q25 is associated with a badprognosis for patients because of this correlation with lowerprogression-free survival and overall survival [27].

Finally, it has been defined that 9q33–34 is the region withthe most frequent gains and its occurrence correlated signifi-cantly with relapse [27]. We found a greater incidence at re-lapse compared with the initial diagnosis for a gain at 1q,9q34, 15q22, and 18q21, and losses at 6q [27, 30].

Regarding the genes reported to have changes in methyla-tion, we found that the most frequent genes were CHIBBY,RAC2, and hTERT, in 8.8%, 9.2%, and 27.8% of the cases,respectively. It is possible that loss of RAC2 function has agreater impact in younger patients, whose central nervous sys-tem is still under development. It has been reported in EPs thatthe CHIBBY promoter has a high frequency of methylation.The downregulation of CHIBBY in cancer cells might provideinformation regarding the use of CHIBBY as a therapeutictarget and prognostic factors have been associated with tumor-igenesis [22, 43]. Furthermore, the results suggested that apartfrom less aggressive molecular subtypes, hTERT promoterhypomethylation might characterize intracranial ependymal

tumors with a more favorable outcome [41]. It has even beensuggested that hTERT and CHIBBY methylation changes arecharacteristic of pediatric ependymomas, but they are not yetassociated with the patient’s prognosis. Furthermore, the CpGisland methylator phenotype in EP proposed by Mack et al.[37] allows us to stratify these tumors in PFA-CIMP+ andPFB-CIMP−, thus highlighting the distinct epigenetic differ-ences among them.

In relation to gene expression, we found the hTERT, ERBB,ERBB1, ERBB2, ERBB3, STB, SHC1, and TPR genes wereoverexpressed. In several publications, a series of characteris-tic and prognostic molecular markers have been suggested,but no consensus on the matter has been reached. However,it has been reported that ERBB1, ERBB2, ERBB3, and ERBB4are important in the development of EP and participate in cellproliferation [16]. Witt et al. [44] classify EPs into two tran-scriptionally defined main subgroups: PFA and PFB; Group Atumors arose in younger patients (median age 2.5 years)whereas Group B tumors occurred predominantly in olderpatients (median age 20).

Moreover, it has been proposed that inhibition of telomeraseenzymes is associated with an increased progression resulting inthe lack of proliferation, self-renewal, and tumorigenicity; thesefindings suggested that the telomerase can be used as prognosticmarker and therapeutic target in pediatric EP [34]. By exploringmolecular mechanisms, telomerase activity has been describedas a characteristic potential biomarker, showing an associationof telomerase reactivationwith a chromosome 1q gain andRelAfusion [41]. According to our analysis, considering the biasesanalysis, OR, and HR value, the hTERT and ERBB genes arecharacteristic in pediatric EP, but only hTERT can be correlatedwith the prognosis. The hTERTexpression can be used to dividethe resected tumors into good and bad prognostic groups be-cause the EP lacking telomerase activity are unable to maintaintelomeres and proliferative indefinitely, suggesting that less ag-gressive therapeutic intervention may be offered for childrenwith telomerase-negative tumors [21, 34].

About protein expression, several research groups haveproposed different proteins as features of ependymomas andas potential prognostic biomarkers. A previous study sug-gested an association between the overexpression of PDGFRprotein, in tumor and in the tumor endothelia, has been pre-sented that overexpression of PGDFRs could have a goodprognostic role in EP [33]. It has been observed that EPsshowed at least focal immunopositivity for MDM2, and onlysome showed immunopositivity for P53. These findings areconsistent with previous reports describing ependymomasrarely have P53 gene mutations and that neoplasms withMDM2 amplification typically lack P53mutations that dereg-ulate the cell cycle [11]. Our findings correlate with Guptaet al. [35]; the proteins NOTCH-1, TN-C, and Hes-1 showeda significantly higher expression in grade III tumors in com-parison to grade II tumors.

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Conclusion

The general results suggest that protein expression plays animportant role in pediatric ependymomas and that it can beconsidered as a possible molecular biomarker of prognosis.Chromosomes 1q and 22q are features in pediatric EP, andthe gain at 1q25 has a high probability of being used as aprognostic biomarker. When considering the poor prognosisand survival rate of patients, the hTERT gene changes in ex-pression and methylation status may play an important role inthe development of pediatr ic ependymal tumors.Nevertheless, the results should be interpreted with caution.Additional research is needed to assess the true effect of pro-tein expression to identify patients at risk.

Acknowledgments We thank the scholarship CVU 404762 granted fromCONACYT and IMSS 011-2013 for the development of the student, andthe postgrad program of Ciencias Biológicas, from the UniversidadNacional Autónoma de México. We thank the research scholarship ofIMSS Foundation A. C. given to Dr. Normand García Hernández. Wethank the given support to Dr. Fabio A. Salamanca Gómez from Hospitalde Pediatría BDr. Silvestre Frenk Freund,^ IMSS.

Author Contributions All authors contributed to the study conceptionand design. Conceptualization by N.G.-H. and M.P.-R. Material prepara-tion, data collection, and analysis were performed by M.P.-R., T.J.-C.,A.G.-M., and N.G.-H. The first draft of the manuscript was written byM.P.-R. and T.J.-C., and all authors commented on previous versions ofthe manuscript. Supervision by N.G.-H. All authors read and approvedthe final manuscript.

Funding We are grateful for the funding provided by the CONACYTSectoral Funds S0008-2010-1, 142013. We thank the FIS IMSS for thesupport FIS/IMSS/PROT/949, 2009-785-042 and R-2014-785-094.

Compliance with Ethical Standards

Conflict of Interest The authors declare that they have no competinginterests.

Ethical Approval The project was carried out under the authorization ofthe molecular biomarker search protocol for ependymal tumors in pedi-atric patients with registration number R-2014-785-094, at the EthicsCommittee of National Ethics Commission from the Instituto Mexicanodel Seguro Social, IMSS. All data have been kept in strict confidentiality.

Informed Consent The tests were carried out following the rulesestablished in the Helsinki agreement. All participants were duly in-formed and provided their written consent for each of the procedures.

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