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 Table of Contents  
Year : 2018  |  Volume : 4  |  Issue : 5  |  Page : 123-128

Molecular insights turning game for management of ependymoma: A review of literature

Department of Radiation Oncology, Tata Memorial Hospital, Mumbai, Maharashtra, India

Date of Web Publication30-Oct-2018

Correspondence Address:
Dr. Rahul Krishnatry
Department of Radiation Oncology, Tata Memorial Hospital, Parel, Mumbai - 400 012, Maharashtra
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/ctm.ctm_40_17

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Molecular biology of ependymoma is being extensively studied in recent years, providing insights into newer therapeutic strategies. The different anatomic subgroups of ependymoma, namely supratentorial, posterior fossa (PF), and spinal, pose entirely different clinical behavior and prognosis. Recently, nine molecular subgroups of ependymoma have been identified, one of which has been incorporated into the WHO classification. Further understanding of the molecular biology of ependymoma is vital to expand its clinical utility. Here, we performed a review of the literature on the molecular biology of ependymoma. Therapeutic avenues include: (1) targeted agents against – (a) chromothripsis-induced nuclear factor-kappa beta signaling, (b) gene silencing by DNA methylation, (c) increased telomerase activity, and (d) microRNA and (2) de-escalating treatment in good prognostic subgroup such as PFB. The prognostic value of different chromosomal gain or loss is being better understood and may serve as prognostic signatures in future. Faster adoption of molecular classification into clinical practice requires simpler identification techniques using immunohistochemical surrogates for molecular subgroups, for example, cell adhesion molecule L1 for v-rel reticuloendotheliosis viral oncogene homolog A (RELA) fusion, laminin subunit alpha 2, tenascin-C, and neural epidermal growth factor-like 2 for PFA and PFB. Identification of poor prognostic markers such as RELA fusion and PFA has necessitated future research impetus to be directed to find more efficacious treatment approach in these groups.

Keywords: Biology, ependymoma, molecular, subgroups

How to cite this article:
Sasidharan A, Krishnatry R. Molecular insights turning game for management of ependymoma: A review of literature. Cancer Transl Med 2018;4:123-8

How to cite this URL:
Sasidharan A, Krishnatry R. Molecular insights turning game for management of ependymoma: A review of literature. Cancer Transl Med [serial online] 2018 [cited 2019 Jun 27];4:123-8. Available from: http://www.cancertm.com/text.asp?2018/4/5/123/244521

  Introduction Top

Ependymoma constitutes approximately 10% of pediatric brain tumors and is the third most common tumor after low-grade glioma and medulloblastoma.[1] As per the referral pattern from four major tertiary cancer care centers in India, it is the fourth most common after astrocytoma, medulloblastoma, and craniopharyngioma.[2] In our institute, ependymomas constitute 19.1% of pediatric brain tumors.[3]

Median age of presentation of ependymoma is 2.4 years, and there is a slight male preponderance. Most pediatric ependymomas are intracranial with 80% of them occurring in the posterior fossa (PF). In adults, about 66% occur in the spinal cord and > 50% of the intracranial ependymomas are supratentorial (ST).[4]

Surgery is the primary mode of treatment for ependymoma with gross total resection (GTR) or maximal safe resection being the most important prognostic factor. Adjuvant radiotherapy is the current standard of care in high-grade (II or III) ependymoma. Adjuvant radiotherapy decreases local recurrence following either GTR or subtotal resection (STR).[5],[6],[7] The event-free survival (EFS) and overall survival (OS) at 5 years is 80% and 90% with GTR versus 40% and 50% with STR respectively.[5],[7] The EFS and OS at 10 years is 45% and 60% with GTR and 25% and 30% with STR.[7] Adjuvant chemotherapy, as a strategy to avoid radiotherapy in young children (below 5 years of age), in SIOP study has shown an inferior survival rate, with 4 years EFS and OS rate of 22% and 59%, respectively,[8] irrespective of the extent of surgical resection. Another study by UKCCSG/SIOP on adjuvant chemotherapy in children < 3 years with intracranial ependymoma showed an EFS of 44%.[9] In comparison, adjuvant radiotherapy in children < 3 years has shown EFS of 68%.[5] Hence, the role of chemotherapy remains inconclusive in young children with ependymoma.

  Understanding the Biology Top

The biology of ependymoma has remained an enigma for clinicians. Despite the similar histology and grade, ependymoma behaves differently in different age groups and with respect to location of the tumor.[10] Prognosis of ependymoma is positively associated with increasing age of the patient. Infants have a poorer five-year survival of 40%–50% compared to adults who have a better five-year survival of 80%–90%. ST ependymomas have a better prognosis compared to PF ependymomas that are more common in children. Whether these disparities in survival is due to the poorer resectability of PF lesions or lesser use of adjuvant radiotherapy in very young children or due to underlying biology was not well understood.

The 2007 WHO classification, classifying ependymoma into three grades, is found not useful as a robust prognostic classification, owing to poor interobserver variability between Grade II and III ependymoma, with high concordance rate of 69%, between pathologists.[11],[12] Grade I ependymomas, showing good prognosis predominantly in adults, includes myxopapillary ependymoma which usually arises in spinal cord and subependymoma which can occur in all three compartments. Grade II and III ependymomas are called classic and anaplastic ependymomas but are difficult to distinguish from each other histologically. Moreover, the utility of distinguishing between Grade II and III as a robust prognostic marker is not seen in all clinical settings.[12]

Recently, nine molecular subgroups of ependymoma were identified in a large cohort of 500 tumors, and they outperform the current histological classification in associating clinical condition with the outcome.[13] The molecular subgroups can be categorized based on their location – ST, PF, and spine. The new consensus on management of intracranial ependymoma recognizes that the treatment decisions for ependymoma should not be based on histopathological characteristics alone and that the molecular classification should be a component of any future clinical trial.[14] Meanwhile, the 2016 update for the WHO classification of central nervous system tumors has accepted one genetically defined subtype: ependymoma, v-rel reticuloendotheliosis viral oncogene homolog A (RELA) fusion-positive.[15]

  Understanding the Molecular Biology of Ependymomas Top

Fusion of genes through chromothripsis

Chromothripsis is the phenomenon by which thousands of clustered chromosomal rearrangements occur in a single event, in localized and confined genomic regions, and in one or a few chromosomes. The chromothripsis phenomenon opposes the conventional theory that cancer is the gradual acquisition of genomic rearrangements and somatic mutations over time and was first observed while sequencing the genome of a chronic lymphocytic leukemia patient. Single nucleotide variations, insertions and deletions, or focal (< 5 genes) copy number alterations are rare in ependymomas, but structural variations (SVs) are detected relatively frequently in ST ependymomas. Using a technique called “clipping reveals structure,”[16] the ST ependymomas have shown SVs clustered within 11q12.1–q13.3, an oscillating copy number state characteristic of chromothripsis. Although the chromothripsis region differed among tumor, most (70%) shared a common region in which the reordered chromosome fragments fused a poorly characterized gene-chromosome 11 open reading frame 95 (C11orf95) to RELA, the principal effectors of canonical nuclear factor kappa-light-chain-enhancer of activated B-cells (NF-kB) signaling. The C11orf95-RELA fusion protein translocates spontaneously into the nucleus and activates.

NF-kB genes, and rapidly transforms neural stem cells to ependymal stem cells. NF-kB upregulation leads to increase in antiapoptotic factors. Most of the ST ependymomas harbor C11orf95-RELA fusion and can be identified by fluorescence in situ hybridization, however, in infants, YAP1 fusion (a transcriptional coactivator) is enriched.[17]

Gene silencing by DNA methylation

DNA methylation is an epigenetic alteration caused by addition of methyl groups to cytosine base, changing the activity of the DNA segment without changing the sequence. It is mediated by DNA methyltransferase enzyme which transfers methyl group to cytosine, found within cytosine–phosphate–guanine dinucleotides (CpG), to form 5-methylcytosine. “CpG island methylator phenotype” has been extensively studied in colorectal cancer and has been identified in other cancers including gliomas. Hypermethylation causes gene silencing and decreases the expression of a number of tumor suppressor genes. ST and spinal pediatric ependymomas have hypermethylated phenotype leading to expression changes in genes involved in DNA repair and regulation of inflammation, namely, c-Jun N-terminal kinases pathway and peroxisome proliferator-activated receptor gamma.[18] The data suggest that hypermethylation-induced epigenetic gene silencing is an important mechanism in the pathogenesis of ST and spinal ependymomas. However, in PF ependymoma, CpG-island (CpGi) hypermethylation has been identified; they are targeted by polycomb repressor comple × 2 (PRC2), containing enhancer of zeste homolog 2 (EZH2) which causes trimethylation of lysine 27 on histone H3 protein subunit (H3K27 me3) analogous to H3K27M-mutant gliomas, resulting in lowered H3K27 me3 in ependymomas with CpGi methylation.[19] This had led to division of PF ependymoma into two subgroups: PFA and PFB, with PFA having relatively more CpGi hypermethylation compared to PFB. Beyond the CpGi regions, a global hypomethylation is evident in PFA tumors. PFA ependymoma has a worse prognosis than PFB across the entire age spectrum, and frequently relapse even after GTR and adjuvant radiation therapy. PFA patients are usually younger children, while PFB affects older children and young adults with none below 5 years of age. A vast majority of children under the age of 10 are PFA ependymoma, with a 50:50 split in adolescence, and only 15% of adult PF ependymoma being PFA subtype. In a population-based study, the 10 years OS in children < 3 years of age was 61% with GTR and 38.2% and 35% with STR and biopsy, respectively.[20] The patients with PFB undergoing GTR have an excellent 10-year OS of 90%. Even without “upfront postsurgery external beam radiation,” this group shows a good OS, with successful salvage of relapse with radiation.[21]

Increased telomerase activity

Telomeres are repetitive nucleotide sequence of TTAGGG, with complementary AATCCC, with single-strand TTAGGG overhang. This prevents DNA ends being recognized as DNA breaks. Telomeres of proliferating cells become shorter and shorter with ongoing cell division synonymous to cellular clock to aging, till they become dysfunctional, resulting in higher genomic instability and growth arrest. Telomere maintenance is one of the hallmarks of cancer. Human telomerase reverse transcriptase (hTERT) is essential for telomerase production and telomere maintenance. There is a correlation between MIB-1 proliferative index of > 12% and tumor grade, as 63% Grade 2 ependymomas and 11% Grade 3 ependymomas are hTERT negative. Correlating hTERT expression and DNA damage (¥H2AX as surrogate) with outcome in ependymoma has shown 5-year progression-free survival (PFS) and OS of 69±15% and 100%, respectively, in hTERT(−)/¥H2AX(+) patients versus 17%±8% and 22%±9%, respectively, in hTERT(+)/¥H2AX(−) patients.[22] Telomerase enzymatic activity can serve to subgroup PF ependymoma, particularly the PFA group, into better and worse prognosis groups.[23]

Chromosome gain or loss

The single molecular marker that has repeatedly shown an association with unfavorable outcome is gain of chromosome arm 1q, particularly in PF ependymomas of children.[24] Chromosome 1q gain alone can be seen in up to 24% of pediatric ependymomas and 8% of adult ependymomas. Two studies have shown that “1q gain” is an independent prognostic factor in determining PFS,[25],[26] with one of these studies showing its correlation with OS also.[26] The most common genetic abnormality seen in ependymomas includes 6q loss and 5p gain, seen in about 60% and 40% of the cases, respectively. Prognostic value regarding 6q loss and 5p gain is not yet conclusive.[27] Losses at 22q are frequently seen in NF2 associated intramedullary spinal ependymomas.[28] Gain of dual phosphatase specific locus 12 in chromosome 1q, epidermal growth factor receptor (EGFR) in chromosome 7p, and hTERT in chromosome 5p have been identified in ependymomas. EGFR overexpression in ependymomas is seen not only due to chromosomal gain or gene amplification but other factors as well.[29] Tumor protein-53 (TP53) gene is located in short arm of chromosome 17. Amplification of mouse double minute-2 homolog (MDM2) in chromosome 12 results in inhibition of TP53 in ependymomas, resulting in tumorigenesis.[30] Other gains frequently seen are of ARHGEF5 gene at 7q and HOXC4 gene at 12q.[29]


MicroRNAs (miRNAs) are small noncoding RNAs that have no protein-coding capacity and act by blocking translation of messenger RNA (mRNA), and thus regulate gene expression. High-grade ependymomas have been shown to have increased levels of miRNA expression.[31] miRNA expression profiling has shown that ependymomas of different locations exhibit different miRNA profile. miRNA-203 (located in chromosome 14q32) downregulation is strongly associated with “time to relapse” in ependymoma. Upregulation of other miRNAs located in 14q32, such as miRNA-432, miR-411, miR-376a, miR-381, and miR-487b, was associated with lower relapse-free probability.[32] miRNA 29a/c has been found to be a key regulator of laminin subunit alpha 2 (LAMA2) expression seen in PF ependymoma.[33] Therefore, miRNAs seem to be an additional promising candidate as a prognostic marker in ependymoma.

  Immunohistochemistry Surrogate for Molecular Subgroups Top

Most of the molecular testing in ependymomas is beyond the routine facilities available with usual pathology laboratories across the world. If something as simple as immunohistochemistry (IHC) can find a good surrogate for current complex molecular information, then it would be practically feasible to incorporate molecular information in routine clinical practice.

RELA fusion leads to an increased expression of neural cell adhesion molecule L1 (L1CAM) protein, and there is a high concordance of predicting RELA fusion using L1CAM IHC.[34] Immunohistochemical expression of LAMA2 and neural epidermal growth factor-like 2 may serve as markers for PFA and PFB tumors, respectively, while high tenascin-C expression can be related to PFA tumors.[35] The pediatric ependymoma protein database has identified > 5000 proteins and > 25,000 peptides for every analyzed sample of ependymoma.[36] Identification of newer and more specific biomarkers of different molecular subgroups is hoped to bring about a radical change in the way ependymoma is evaluated.

  Potential Therapeutic Strategies in Ependymoma Top

In ependymoma, a chemoresistant tumor, surgery and adjuvant radiotherapy is the standard of care. In view of excellent prognosis, adjuvant radiotherapy may be avoided in PFB tumors after maximal safe resection.[7] Among chemotherapeutic drugs, only bolus 5-FU has shown some antitumor activity and was tested in recurrent pediatric ependymoma though the response was not very promising.[37] BCL-2 (antiapoptotic) inhibition is being tested as a potential therapeutic approach in the light of it being significantly induced by C11orf95-RELA fusion protein. In a study targeting the JAK-STAT pathway, associated with apoptosis, STAT3 inhibitor WP1066 molecule has shown to decrease BCL-2, although the reduction in another antiapoptotic protein “survivin” also occurred, which correlated with apoptosis in the ependymal cells.[38] Pediatric ependymomas are more aggressive tumors, with most of them located in PF. Epigenetic modifiers, inhibiting PRC2 using small molecule inhibitors of EZH2 such as 3-deazaneplanocin A (DZNep), decitabine (DAC), and GSK343, could be potential therapeutic target agents in PFA.[39] The FDA approved decitabine (DNA methylation inhibitor) has shown significant antineoplastic effect under in vitro culture condition using cells derived from PFA patient and may serve as a potential therapeutic drug for these tumors in future.[40] DNA methylation inhibitors have been approved for use in leukemia (5-azacytidine and deoxy analog of 5-azacytidine). Vorinostat, a histone deacetylase inhibitor, has shown in vitro to induce differentiation in the ependymal stem cells.[41] Telomerase inhibition using MST-312 in in vitro cell lines increased DNA damage (¥H2AX expression) and decreased proliferative index (MIB-1) with half of the cells showing increased apoptosis (cleaved caspase 3), suggesting of a future promise as telomerase inhibition-based therapy.[42] EGFR inhibitors AEE788 and gefitinib have shown reduction in proliferation and survival of ependymoma stem cell lines. Orally administered AEE788 improved survival in mice bearing ependymoma stem cell-driven orthotopic xenografts, from 56 to 63 days (P = 0.06).[43] Phase I clinical trial of gefitinib in refractory pediatric solid tumors established a maximum tolerated dose of gefitinib as 400 mg/m2/day. In the study, one patient with ependymoma developed intratumoral bleeding at a dose of 500 mg/m2/day on the 18th day of treatment.[44] A Phase II study comparing erlotinib (85 mg/m2/day) versus etoposide in refractory pediatric ependymoma was stopped after interim analysis due to the futility of efficacy. None of the patients in the erlotinib arm had an objective response, whereas some patients in the etoposide arm responded to the treatment (NCT01032070). Combining EGFR targeting agents with radiotherapy seems to be a potential therapeutic option. In a preclinical study with 9 pediatric ependymoma xenografts, 5 cases (55.5%) showed complete response and 4 cases (44.5%) showed partial response when treated with 1 Gy of irradiation followed by gefitinib (100 mg/kg for 5 consecutive days).[45] However, Phase I or II clinical studies of EGFR inhibitors with radiotherapy are lacking. MDM2 inhibition using low-dose actinomycin-D has shown p53 reactivation at RNA, protein, and functional levels in preclinical high-risk ependymoma models.[46] Antisense miRNAs, which are potent oligonucleotides targeted against overexpressed miRNA and replacement of loss-of-function miRNAs,[47] are novel therapeutic strategies which are yet to be explored in ependymoma.

  Conclusion Top

Prognostication based on molecular subgroups will help in tailoring the treatment of ependymoma on an individual basis. Incorporating and validating surrogate immunohistochemical markers for different molecular subgroups would ensure faster adaptation of molecular classification into routine clinical practice. Understanding molecular biology and exploring novel targets for treatment is bound to change the management of ependymoma in the near future.

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Conflicts of interest

There are no conflicts of interest.

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