Neurosurg Focus 35 (6):E5, 2013

©AANS, 2013

A review of epigenetic and gene expression alterations
associated with intracranial meningiomas
Shuhan He, B.S.,1 Martin H. Pham, M.D.,1 Matthew Pease, B.S.,1 Gabriel Zada, M.D.,1
Steven L. Giannotta, M.D.,1 Kai Wang, Ph.D., 2,3 and William J. Mack, M.D.1,3
Departments of 1Neurosurgery and 2Preventive Medicine, and 3Zilkha Neurogenetic Institute, Keck School of
Medicine, University of Southern California, Los Angeles, California

Object. A more comprehensive understanding of the epigenetic abnormalities associated with meningioma tu­
morigenesis, growth, and invasion may provide useful targets for molecular classification and development of tar­
geted therapies for meningiomas.
Methods. The authors performed a review of the current literature to identify the epigenetic modifications associ­
ated with the formation and/or progression of meningiomas.
Results. Several epigenomic alterations, mainly pertaining to DNA methylation, have been associated with me­
ningiomas. Hypermethylation of TIMP3 inactivates its tumor suppression activity while CDKN2 (p14[ARF]) and
TP73 gene hypermethylation and HIST1H1c upregulation interact with the p53 regulation of cell cycle control. Other
factors such as HOX, IGF, WNK2, and TGF-b epigenetic modifications allow either upregulation or downregulation
of critical pathways for meningioma development, progression, and recurrence.
Conclusions. Genome-wide methylation profiling demonstrated that global hypomethylation correlates with
tumor grades and severity. Identification of additional epigenetic changes, such as histone modification and higher-
order chromosomal structure, may allow for a more thorough understanding of tumorigenesis and enable future
individualized treatment strategies for meningiomas.
(http://thejns.org/doi/abs/10.3171/2013.10.FOCUS13360)

Key Words      •      meningioma      •      epigenetics      •      methylation      •      acetylation      •     
genomics

M
eningiomas, which originate from the arachnoid­ to sampling error and inter-user variability.38 Additional
al cap cells of the leptomeninges, have an in­
50
possible explanations for the difficulty in predicting the
cidence of 4.4 per 100,000 person-years74 and behavior of meningiomas have included the observations
are the most commonly diagnosed primary brain tumor.22 that there are numerous histological similarities between
The peak incidence of meningiomas occurs in the 6th and tumors in each grade and that these tumors exist along a
7th decades, and women are affected nearly twice as of­ spectrum in which low-grade meningiomas can progress to
ten as men.48 a higher grade.2 There is no clear explanation, however, as
Meningiomas are often organized with the WHO clas­ to why the majority of recurrent meningiomas derive from
sification of tumors, with 80% being considered Grade benign histology even after apparently radical removal.55
I (benign); 10%–15%, Grade II (atypical); and 2%–5%, Other attempts to classify meningiomas have used
Grade III (anaplastic/malignant).9 Grade III meningiomas genomic techniques to study their genesis and progres­
are typically associated with brain invasion and recur­ sion,73 as well as to search for genetic mutations and
rence, and the overall 10-year survival rate for patients with variable gene expression mediated via epigenetic modi­
these lesions is only 14.2%.22 Thus, it is of critical clinical fications.35 The use of epigenomics as a clinical tool has
significance to accurately determine the characteristics of become better understood in recent years47 and research
these tumors in a timely fashion. The WHO pathological has started to elucidate the importance of epigenetics in
grading system cannot always accurately predict the clini­ meningioma progression. Data suggest that there is an
cal aggressiveness of these tumors, and grading is subject absence of any significant genetic alterations in nearly
40% of meningiomas.31,52 One study found that 77% of
Abbreviations used in this paper: MMP = matrix metalloprotein­ meningiomas had at least 1 methylated gene, and 25%
ase; p53 = tumor suppressor p53 (cellular tumor antigen p53); uPA of samples in another study had 3 or more methylated
= urokinase plasminogen activator. genes.5 Epigenetic alterations in the genome are also par­

Neurosurg Focus / Volume 35 / December 2013 1

that could provide significant (Table 1). and recurrence. Of these studies.  Two possible mechanisms for oncogenesis via epigenetic modifications.   Lower: A nor- mally unmethylated tumor suppressor gene becomes methylated through epigenetic modifications. He et al. and recurrence The best understood of the tumor suppressor genes of intracranial meningiomas. S. using all combinations of the search terms meningioma phenotype. which encodes for a avenues of molecular classification. To be considered eligible for inclu­ functions via extracellular matrix proteolysis to facilitate sion.1 intersecting with sequence. Increased expression of uPA pro­ teins is associated with higher WHO grade. which degrades the extracellular that are not accompanied by changes in the primary DNA matrix and activates various MMPs.4. allowing runaway cellular growth.3 Overexpression of TIMP3 in vitro has been Methods shown to suppress tumor growth and induce apoptosis. Two investiga­ TIMP3 than Grade II or III meningiomas. ticularly useful to examine because they are thought to publication in a language other than English. In this review.7 Hypermethylation of the 22q12 gene TIMP3 and subse­ A systematic review of the PubMed database was quent transcriptional downregulation (gene silencing) has performed to identify all studies published up to Au­ been identified as a marker for an aggressive. progression. p53) is a ubiquitous component in growth regulation criteria.” disagreement in the literature. high-grade gust 2012. inhibiting transcription and thus leading to proliferation of meningioma through loss of function. prognosis.5 tors independently screened all identified abstracts for The urokinase plasminogen activator (uPA) system potential inclusion.” Only English-language found to have significantly less aberrant methylation at publications were included in our query.40. a study looked at the epigenetic changes to menin­ cellular adhesion and migration. 1).85 A primary and secondary review of all identified ab­ TP53.35 the pathway of TIMP-3. 2 Neurosurg Focus / Volume 35 / December 2013 .51 Active uPA activates giomas defined as alterations in levels of gene expression plasminogen to plasmin.” “epigenetics. and epi­ protein that inhibits matrix metalloproteinases (MMPs) genetic therapies (epidrugs).” “methylation. The result­ occur in the early stages of tumorigenesis35 and can func­ ing 26 studies from the systematic search were then clas­ tion through multiple mechanisms to cause runaway cell sified according to gene subtype affected by epigenetic growth (Fig.   Upper: A proto-oncogene is demethylated. we present a systematic analysis of the genes that are known to undergo epigenetic modifications Tumor Suppressor Genes as related to the development. Grade I tumors have been “sequencing. 112 were discarded due to 1) that interacts with multiple other pathways to control the identified changes in the underlying DNA sequence or 2) cell cycle. Loss of chromosome 9 is of particular impor­ Fig. This article summarizes the as pertaining to epigenetic regulation of meningiomas is literature pertaining to the epigenetic modification of the TIMP3 (TIMP metallopeptidase inhibitor 3 or tissue meningiomas and provides a brief discussion for future inhibitor of metalloproteinase 3).” “histone.49 Although there is some minor “meningioma. allowing for transcription factors to bind and express the oncogenic product. malignant Results invasion. Tumor suppressor p53 (cellular tumor antigen stracts resulted in 138 studies that met initial inclusion p53. A second function appears to be a unique tu­ clinical value to patients with meningiomas in the future. modification. 1. mor suppressor–like property that is not related to MMP inhibition.” and “acetylation.

which neutralizes it and allows its terns.83 and is fre­ cated at 14q32. Inac­ sion and immunohistochemistry as having a stronger ex­ tivation of this p14ARF and p53 pathway through hyper­ pression profile in atypical and anaplastic meningiomas methylation has been shown to occur frequently in human than benign meningiomas: PCNA. and brain tumors. The study illustrates the are important components of the progression of atypi­ importance of epigenetic regulation of p53 as a key inhibi­ cal and anaplastic meningiomas.2 upregulation cell cycle recurrence2 MEG3 14q32 noncoding RNA hypermethylation cell cycle tumorigenesis & grade3 tance because of 3 notable tumor suppressor genes lo­ ity of meningiomas. through mRNA expres­ prevents the normal cell cycle checkpoint function. The concordant methylation of HOXA candidate for epigenetic meningioma progression.49 pression that encodes a noncoding RNA.45 used high-throughput Neurosurg Focus / Volume 35 / December 2013 3 . in a study by Pérez-Magán et al.038) as well.98 hypothesized that since MEG3 is lo­ for gene silencing via DNA comethylation21.2 pro­ cogenic tissue. similar to the rate of allelic losses. STK15 (AURKA). 58 Epigenetic studies encodes mitosin. CDK2NA (p14[ARF]) is a gene on quently show a higher degree of MEG3 methylation (p = the 9p21 locus that interacts with TP53 and regulates the 0.33 Hypermethylation may suppress p53-dependent p300-mediated chromatin of GSTP1 was found with an increasing frequency from transcription by blocking chromatin acetylation.69 It is hy­ is downregulated in recurrences compared with nonon­ pothesized that the physical interaction of the H1.45 Kishida et al.8 The p14ARF (cyclin. it would be an ideal esis76.22 TMEM30B 14q transmembrane factor hypermethylation cell cycle recurrence2 HIST1H1C 6p21. whereas enhanced p73 expres­ gies. a portant role in malignant meningiomas. ously been found to be expressed in meningiomas41 and respectively. similar to increases previously the degradation of p53.17 GSTP1 is a member of the glutathione- tein can participate in the epigenetic regulation of gene S-transferase family.Epigenetic and gene expression alterations in meningioma TABLE 1: Tumor suppressor genes Gene Locus Product Modification Function Effect TIMP3 22q12. caus­ nificant sequence homology with p53. a protein of centromere-kinetochore show that p73 plays a similar dual role in meningioma complex protein that is involved in cell division of so­ progression. whereas high-grade meningiomas fre­ cated on its short arm.15 CDKN2A (p14[ARF]) 9p21..86 sion characterizes malignant meningiomas. MEG3 (ma.11 It had previ­ 27% and 89% of original and recurrent meningiomas. Its function is to conjugate carcino­ expression by maintaining specific DNA methylation pat­ gens with glutathione. Previous mu­ ed in vitro on meningioma cell lines.100 Zhang et al.39 also plays an im­ ing cell proliferation. Histone cluster 1.24 More specifically. TEME30B HIST1H1c.90. a region that has been previously associ­ quently identified in a wide variety of human tumorigen­ ated with meningioma progression.99 Methylation and inhibition of found in pancreatic carcinomas. including HOXA5. isoform 4) protein binds Atypical anaplastic meningiomas show higher ex­ to the MDM2 oncogene (MDM2) and promotes the rapid pression of the GADD45A gene94 when compared with degradation of the MDM2 regulator protein. the authors hypothesize that it excretion. HOXA6.56 STK15 encodes aurora kinase A. preventing DNA damage. Their genes on 7p15.14.28 while CENPF both cell growth and cell cycle arrest.22 Previous re­ centrosome-associated serine/threonine kinase previous­ search has indicated that p73 has opposing functions of ly shown to be amplified in colon cancer.96 Three additional genes this pathway consequently increases p53 breakdown and were identified by Wrobel et al. Hypermethylation may cause development matic cells and involved in a range of oncogenic patholo­ of some low-grade forms. which shares sig­ and functions as a cofactor for DNA polymerase. H1c is a gene on chro­ is a gene in the 14q region that encodes a transmembrane mosome 6 that has been found to be overexpressed in factor that participates in the cell cycle. the gene was found tational studies of CDK2NA (p14[ARF]) have shown that to suppress colony formation by 80%.3 P14ARF protein hypermethylation cell cycle control tumorigenesis1 TP73 1p36 P73 protein hypermethylation cell cycle control tumorigenesis14. preventing benign meningiomas.2. when MEG3 cDNA was test­ transition from the G1/S-phase checkpoint.95 (Table 2). research showed that MEG3 RNA is highly expressed in and HOXA11 leads to the downregulation of tumor sup­ normal arachnoidal cells but not expressed in the major­ pressor targets. HOXA9. and velopment and grade extends to another gene. an imprinted gene with maternal ex­ ated with meningioma grade. Furthermore.44. Previous research showed that MEG3 RNA functions by activating p53 target Cell Signaling genes and stimulates p53-mediated transcriptional activa­ The homeobox (HOX) family of genes is a target tion.64 Other tumor suppressor genes that do not involve the p53 pathway include TMEM30B and GSTP1.94 PCNA interacts with GADD45A (GADD45) The tumor suppressor protein p73.97 CENPF.1 histone H1. including homozygous deletions at 9p21. other known growth suppressors. 0% in benign to 32% in atypical to 54% in anaplastic The importance of p53 in preventing meningioma de­ variants49 of meningiomas in one study by Liu et al. thus GSTP1 promoter region hypermethylation is associ­ ternally expressed 3). tor of meningiomas. dependent kinase inhibitor 2A.3 metalloproteinase inhibitor 3 hypermethylation MMP inhibition higher meningioma grade14.

3 LIM domain transcription downregulation transcription factor tumorigenesis2   factor LMO4 CTGF 6q23. showed that have also been reported in metastasis of colorectal neo­ WNK2 could be reactivated with a methylation inhibitor plasms. one vitro by negatively modulating the activation of MEK1/ of a group of transmembrane proteins that form complexes ERK1/2 and epidermal growth factor receptor (EGFR) on the surface of bladder epithelium.80 Although its role in oncogenesis is still relative­ in 13 other tumor types. Jun et al. and such alterations enhance EGFR protein signaling. heart.1–p34 alkaline phosphatase downregulation cell cycle control progress & grade9 THBS1 15q15 thrombospondin 1 methylation angiogenesis inhibition angiogenesis1 genome-wide DNA methylation analyses of high-grade ing. EGFR is thought to be an important oncogene of the promotor region of UPK3A is the primary mecha­ in meningiomas. HOXA6.102 DNA methylation signaling.2 CTGF hypermethylation growth factor recurrence2 CTNNB1 3p21 β-catenin downregulation Wnt signaling cell growth & tumor aggressiveness8 CDK5R1 17q11.92. and IGF-binding pro­ NDRG2. S. UPK3A codes for uroplakin-3a.. These candidate genes have been identified as meth­ WNK2. The literature has cle and is one of 4 members of the NDRG family.31 uroplakin-3a hypermethylation growth factor tumorigenesis4 IGFBP3 7p13–p12 insulin-like growth factor upregulation growth factor cell growth & tumor aggressiveness5   binding protein 3 IGF2 11p15.2 HOXA5. PENK has been was aberrantly methylated in 83% and 71% of Grade II identified in other genome-wide analysis of various solid and III meningiomas. It is hy­ genes potentially implicated in meningioma progression. pothesized to play a role in tumorigenesis by stabilizing These genes included HOXA6 and HOXA9 as identified messenger RNAs of the c-myc oncogene and IGF2 in cer­ previously by Di Vinci et al. comethylation transcription factor tumorigenesis4   HOXA9.94 It was reported sets of diverse meningiomas. while expres­ to regulate stress-induced apoptosis. & HOXA11   HOXA9. IGFBP1 is an RNA-binding protein and high-recurrence meningiomas. and thus their findings may be trans­ latable to the bedside. concordance with previous evidence that p53-related path­ implicating it as a potential cell growth suppressor.10.60 Jun et al. The authors noted that aberrant ly unknown. & HOXA11 PENK 8q23 preproenkephalin hypermethylation apoptosis tumorigenesis4 UPK3A 22q13. IGFBP3 and IGF2 transcripts.21 along with genes PENK tain cancers. N-myc downstream regulated gene 2 teins have been demonstrated as a key signaling pathway (NDRG2) is normally expressed in brain.2 CDK5R1 protein upregulation Wnt signaling cell growth & tumor aggressiveness5 ENC1 5q12–q13. and WNK2 silencing could potentially nism underlying silencing of the gene. and identified several that regulates mRNA stability and translocation. The IGF signaling family and the anomalous expression of IGF. respectively.3 ENC 1 protein upregulation Wnt signaling cell growth & tumor aggressiveness5 CCND1 11q13 CCND1 protein upregulation Wnt signaling cell growth & tumor aggressiveness5 ALPL 1p36.45 and UPK3A. is important in meningioma progres­ downregulated in Grade III meningioma and independent sion and anaplastic classification.75 It consistently revealed that the increased expression of has been implicated in cell growth as well as apoptosis. He et al.37. TABLE 2: Cell signaling Gene Locus Product Modification Function Meningioma Effect HOXA5.2 NDRG2 protein hypermethylation transcription factor cell growth & tumor aggressiveness7 LMO4 1p22. along with decreased ex­ and identified by Lusis et al. The loss of NDRG2 expres­ that IGFBP3 may potentiate IGF1 action by altering B/ sion was significantly associated with hypermethylation AKT protein kinase sensitivity to IGF-1 receptor signal­ of the NDRG2 promoter. HOXA6.36 in IOMM-Lee cells. IGF. IGF receptor. 7p15.31 WN kinase hypermethylation growth factor tumorigenesis NDRG2 14q11. but rarely methylated tumors.5 IGF-2 protein upregulation growth factor cell growth & tumor aggressiveness6 IGFBP2 2q33 insulin-like growth factor upregulation growth factor cell growth & tumor aggressiveness4   binding protein 2 IGF2BP1 17q21.54 4 Neurosurg Focus / Volume 35 / December 2013 .32 RNA binding protein hypermethylation transcription factor tumorigenesis4 WNK2 9q22.65.12 Furthermore. as a gene that is consistently pression of IBFBP2.57 This would seem in sion of exogenous WNK2 inhibited colony formation. a recent study suggested that cellular stress methylation of the CpG island was associated with de­ induces PENK to physically bind with p53 and RELA (p65) creased gene expression in primary tumors. found that WNK2 ylation targets in various other tumors. In meningiomas. and mus­ in the tumorigenesis of meningiomas.71 ways play an important role in meningioma epigenetically WNK2 has been shown to inhibit cell proliferation in mediated oncogenesis.

The Notch pathway is another signaling cas­ permethylation of the SFPR1 promoter has been noted to cade that has been implicated in tumorigenesis through have a similar effect in gliomas.79. Immunohistochemi­ cal ten in original meningiomas (32%) than in normal menin­ stud­­ies have previously demonstrated that anaplastic me­ gothelial tissue. found that 54% of Grade III meningiomas and 30% searchers found a novel alternatively spliced LIF mRNA. Neurosurg Focus / Volume 35 / December 2013 5 .79 explaining previous immunohisto­ gest that LMO4 modulates TGF-b signaling through its chemical studies that have shown this very reduction.101 and pancreatic tumors63 and CK5. Findings from an analysis of 10 human me­ ferase-2 (NAT2) alleles for meningioma and astrocytoma ningiomas indicate that MAPK is constitutively expressed growth. 5 respectively. ity without changing levels of unphosphorylated MAPK (p44) and MAPK (p42) in most of the cell cultures.05–3.11 whose product is a growth the family of frizzled-related proteins.69 Hy­ Notch.53 factor in the nucleus for multiple genes for the Wnt sig­ Involvement of the TGF-b–SMAD pathway seems to naling pathway. Located at the 22q chromosomal mally inhibits angiogenesis by disrupting the motility of region.69 are mediated by beta catenin. In one study. yet undefined role in meningioma The LIF locus encodes a factor that acts upstream oncogenesis. although in recurrences of meningiomas ningiomas frequently lose E-cadherin expression.16 These findings corroborate tyltransferases bind various compounds to a primary aro­ prior work showing that HES1 is upregulated in menin­ matic amine or hydrazine structure and have been linked gioma compared with control dural specimens. Subsequent inhibition of MAPK activity also 1. Indeed. is able to down­ factor secreted by vascular endothelial cells and has vari­ regulate Wnt signaling by forming an inhibitory complex ous regulatory functions in cell growth and apoptosis.34 so play an important. The gene LMO4 (1p22. and upstream signaling factors of found to be at increased risk of developing meningioma MAPK receptors also act as a mitogen in these menin­ and astrocytomas compared with healthy volunteers (OR gioma cells. 95% CI 1. found that evidence that epigenetic mechanisms may play a key role 45% of meningiomas of all grades have hes family bHLH in the Wnt signaling pathway. of all cases of meningiomas showed hypermethylation of which suggests that the LIF gene may be near a key tumor the THBS1 gene. LMO4 has previously been identified as a gene that is Beta catenin is regulated by the complex of CDK5R1 and overexpressed in breast15. a MAPK inhibitor. suggesting that its inacti­ suppressor locus associated with meningioma develop­ vation could lead to neovascularization of atypical me­ ment. p < 0. it is an area that is noted for its importance to endothelial cells and inducing their apoptosis.46 a key Wnt signaling gene.42 Deregu­ to various primary carcinomas of diverse epithelial tissues lated Notch signaling represents a particularly promising that include bladder cancer and colon cancer. The interaction with receptor-activated SMADs. previously known as induc- tion of hairy and enhancer of Split 1) with overexpression Histone Acetylation of the Notch receptor or the Jagged ligand. produced progressive oma.72 however. Furthermore. with frizzled receptors.61. The thrombospondin 1 (THBS1) gene nor­ of the MAPK cascade. The Wnt signaling pathway plays a central role in meningioma epigenetic research.69 regulated. It is silenced more of­ in meningioma tumorigenesis.05).3) is a novel candidate Wnt.27 N-ace­ meningioma pathogenesis. It has been hypothesized blocked upstream mitogenic stimulation of meningioma that the NAT2 polymorphism may have a local effect on proliferation. the rapid portant transducer of cell growth.84 Cuevas et al.66 Olivera et therapeutic target for meningioma treatment. allow for DNA repair and the dynamic pathway as a critically important genetic alteration in regulation of chromatin structure and function.103 investigated the role of 10 different N-acetyltrans- MAPK. furthering its dysregulation.14.29 Hyper­ meningioma pathogenesis. Individuals carrying rapid acetylation alleles were in meningioma cells.05). and thus further studies to in­ in MAPK phosphorylation and reduced MAPK activ­ vestigate its role in meningioma growth are necessary. supporting levels of beta catenin itself seem to increase a function the finding of the downregulation of the TGF-b pathway of this regulatory pathway to also act as a transcription in recurrent meningiomas. there seems to be is known to function in mesenchymal cell–epithelial cell a reduction in beta catenin–regulated cadherin-mediated interactions.87 The findings in its role in tumorigenesis have not growth inhibition. The authors of the meningioma study sug­ cell-cell adhesion. treatment acetylator genotype has been linked to patients with gli­ with PD098059.43 When CDK5R1 is upregulated. all of the tumor methylation and subsequent silencing of this gene may specimens were hypomethylated at the LIF locus relative therefore promote angiogenesis in tumor cells.67 Bello et to constitutional DNA from the same patients. acetylation. indi­ Angiogenesis cating that MAPK inhibitors may be useful treatments for Epigenetic regulation of angiogenic factors may al­ meningiomas in humans.05. transcription factor 1 (HES1.70 ningiomas and contribute to their progression.59. Its tumor suppressor properties CTGF has been found to have significantly lower expres­ have been noted in many other cancers94 and seem to sion in recurrent meningiomas than in original meningio­ play a role in meninigioma recurrence when it is down­ mas in microarray expression data (p < 0. in also include the CTGF gene. adding to the increasing epigenetic mechanisms.Epigenetic and gene expression alterations in meningioma TGF-β.19.81 SFRP1. strongly suggesting that MAPK is an im­ brain tumors by activating carcinogens.79 which the expression is similar. suggesting that there are multiple mechanisms activating the Notch Histones and their posttranslational modification sys­ tem. The re­ al. correlating with a marked reduction been conclusive. al. as recurrent meningiomas showed significantly lower mRNA levels than in original meningiomas.

The meth­ amine histone modification patterns given antibodies for ylation status of single candidate genes can be screened the specific modifications. separates malignant from atypical and benign tumors. gate whether benign and malignant tumors differ in DNA Aberrant DNA methylation is thought to silence methylation patterns and whether these differences have genes and reduce expression by blocking transcription­ biological and clinical significance. Additionally. The exact mechanism of its role in tumorigenesis. implicating Types of Epigenetic Alteration that DNA methylation patterns may serve as diagnostic biomarkers for malignancy. researchers use 2 approaches to detect technique.52 In addition. atypical. are associated with increas­ approaches have the advantage of examining all alterations ing tumor grades. there DNA methylation in malignant. while in molecular genetics studies of cancer. One exception is the MAL2 gene. MAL2 has hypermethyl­ has been shown to silence and inactivate gene expression ation at a CpG island in its promoter region in malignant downstream. as it only surveys a These techniques were becoming increasingly popular fraction of the possible modifications to that gene. atypical. for example. Additionally. then growth goes unchecked. found that chromosome 1 alkaline phos. Most genes with hypermethylated CpG islands in methylation45—in particular. ability of high-throughput sequencing. which has maintained in an unmethylated state. unlike most previous cancer hypermethylated loci than genetically mutated loci. However. we investigated Epigenetic alterations in the genome often occur in the correlation between methylation and gene expres­ the early stages of tumorigenesis35 through aberrant DNA sion. and malignant meningiomas. This is likely explained by widespread in an unbiased manner. many silencing machinery from polycomb repressor complex genes have promoter regions that are densely populated (PRC) binding to DNA methylation in malignant me­ with CpG dinucleotides. often leading to tumorigenesis. vis-à-vis somatic mutations. we published a silencing of tumor-suppressor genes and pathways. 4C. If the gene is a growth inhibitor or DNA meningiomas. therefore representing de novo gene silenc­ repair enzyme. our goal was to investi­ gioma tumorigenesis. the ChIP-sequencing (ChIP-seq) In general. suggesting the switching of gene sor gene silencing and tumorigenesis. to our also being unable to study the role of additional genes knowledge. Subsequent hyper­ high expression in levels in benign meningiomas but low methylation of these CpG islands at the promoter region expression in malignant tumors. CpG island hypermethyl­ promoter regions are suppressed in both malignant and ation of promoter regions that results in tumor-suppres­ benign meningiomas. it has In addition to methylation.33 In recent years. however. ing induced by DNA methylation. S. Similarly. can be used to ex­ approaches and genome-wide assessments. 5C. it cannot separate atypical and benign tumors.35 Normally. Hi-C for abnormal epigenetic modifications if they have been and ChIA-PET techniques. which combines chromatin immune-precipita­ aberrant epigenetic modifications: single-gene (targeted) tion with next-generation sequencing.26 To our showing that mutations within the genes themselves co­ knowledge. genome-wide methylated loci.62 meningiomas. may al­ phatase (ALPL) was significantly underexpressed in me­ low for a more thorough understanding of tumorigenesis ningioma compared with controls and especially in Grade and enable future individualized treatment strategies for II/III meningiomas compared with Grade I meningioma. remains unclear. these types of studies have not yet been re­ that may contribute to oncogenesis or anaplasia. In­ changes and that aberrant methylation may be a harbinger terestingly. high­ genetics studies that compare DNA methylation patterns lighting the role that methylation plays in early menin­ between tumor and normal tissue. Compared with the al machinery access to DNA. these studies have now become increasingly popular in molecular genetics Gene Methylation Detection Methods studies.18. Earlier this year. gene approach. such as histone modifi­ Müller et al.82 were specifically devel­ previously implicated or prioritized as playing a role in oped for interrogating higher-order chromosomal struc­ tumorigenesis or transformation. this is the first study to explore genome-scale incide with increasing tumor grade. alterations of histone been shown that DNA methylation at non–CpG island modification and higher-order chromosomal structure sites may play as important a role in modulating gene represent additional epigenetic mechanisms that may reg­ expression as methylation occurring at promoter CpG is­ ulate gene expression and function.20. The single- may be located far away (even in different chromosomes). Other Mechanisms of additional epigenetic changes. using techniques such tures between regulatory elements and target genes that as polymerase chain reaction or MethyLight. Discussion Genome-Wide Analysis of Epigenetic Alterations The literature pertaining to epigenetic regulation of meningiomas demonstrates that progressively more In addition to candidate gene studies.77 Larger- ported on meningiomas. 3C. is limited. For example. Because of the avail­ land sites. in general. however. termed CpG islands.6. while hierarchical clustering analysis readily of malignant transformation and recurrence. This study comparing genome-wide methylation patterns in finding is also consistent with findings of previous studies benign. It is expected that identification scale methods for detecting epigenetic involvement in 6 Neurosurg Focus / Volume 35 / December 2013 .35 This suggests that DNA benign tumors. which are ningiomas. the atypical and malignant meningiomas methylation is potentially acquired before phenotypical demonstrate increased global DNA hypomethylation. and benign me­ was a trend for Grade I and II meningiomas to have more ningiomas. He et al.31. cation and higher-order chromosomal structure.

2004 brain tumors. Pham. Zada.13 MGMT. CDKN2C.30 genetic alterations of genes and corresponding changes and the NF2 gene itself was methylated in only 1 of 21 in gene expression that may lead to meningioma devel­ tumors in a separate study. hypermethylated in 1 group of 48 meningioma cases49 Author contributions to the study and manuscript preparation and a separate group of 36 meningioma cases. not seem to develop for RB1. Zada. only 6% of MGMT promoters were rials or methods used in this study or the findings specified in this paper. to fully understand this tumor’s biology. are more likely to affect NF2 ex­ nisms involved in meningioma pathogenesis is needed pression than are epigenetic alterations. Pham.73 NF2 mutations have been de­ in a larger series of tumors with clinical follow-up data tected in more than 50% of all sporadic meningiomas in to ensure that genes are correlated to grade and clinical all pathological grades. even though they serve a similar cell cycle regula­ (TIMP-3) and experimental analysis of its effect on primary tumor growth. proposed that regula­ ning (RLGS).  Barski D. that this mechanism of tumor progression did notta. CDKN2B.49.3 and at 19q1378 as well. Olsen BR. We noted. meningiomas. Iwata K. Pease. that NF2 is not a frequent target of epigenetic modification. 1996 tory function. Drafting the article: He.8 used to study meningiomas.25 An Conclusions analysis of 40 CpG sites within 750 bp of the promoter We present here a comprehensive review of the epi­ regions of NF2 showed no methylation of these regions. CDKN2A. Mack. Sawyer JR.49 However. Future research Other important genes that have been previously into potential primary or adjuvant treatments with de­ noted as significant in meningioma development but not methylating and deacetylating agents will be important found as targets of epigenetic target modification include in elucidating their potential role in the management of ADAM23. Zada.32 Over the past decade. in M. Stangeby CDKN2A (p16[INK4A]) 8. Wang. Mack. Analysis and inter­ grade of the neoplasm. clearly showing that mutation of outcome as well. et al: Loss of heterozygosity. CDKN2B. Smith R.89.17 MGMT include the following. progression. such as chromosomal deletions and discovery of other genetic and epigenetic mecha­ and primary mutations. Wolter M. Our results show that epigenetic and transcriptomic Pease. et al: A review of tissue inhibitor of metalloproteinases-3 as well.  Anand-Apte B. with the associated loss of its mer­ portant to investigate expression profiles of more genes lin protein expression. Bao L. Kadri PA. Giannotta. Brain Pathol 20:623–631. It will be im­ gene located on 22q. the low cogene 19:5413–5418.37. Riemenschneider MJ: a single tumor with any alterations at the CDKN2C locus.  Ahomadegbe JC. Mathieu MC. an active role in meningioma development. Husain M: Malignant progression in meningioma: docu­ gests that methylation of these growth control genes does mentation of a series and analysis of cytogenetic findings. previously re­ ported promoter hypermethylation of MGMT in various Disclosure neoplasms throughout the body. Critically revising the article: He. Hypermethylation and transcriptional downregulation of the This lack of epigenetic modification applied to CDKN2D TIMP3 gene is associated with allelic loss on 22q12. and RB1 (RB). Pravdenkova S. Pham. and recurrence.73 Esteller al. however.5 Loss of CDKN2A.91 Other mechanisms involved opment. Acquisition of data: He. or   1. Vayssade RB1 activity through mutation or methylation would.  Al-Mefty O. Tourpin S. CDK­N2D. Giannotta.88 along with RB1 genes sug­ C. Pham. NF2 plays an important early role in meningioma devel­ opment. Approved the final version of the manuscript on behalf of all authors: He.93 It should be surprising to note.94 pretation of data: He. Wang. allele silenc­ theory. J not play a major role in the development of a majority of Neurosurg 101:210–218. Pham. promoter hypermethylation was also not correlated with Mack. Zelek L.97 CDKN2C (p18[INK4C]) CDK inhibitors   3. Conception and design: He. CDKN2A (p16[INK4A]) and CDKN2B (p15[INK4B]) are genes on the 9p21 locus that References regulate the transition from G1/S-phase checkpoint and interact with and RB1. Boström et al. Zetter do not seem to have any role in meningioma progression B. Reviewed submitted version of manuscript: He. Pease. Additional analysis in loss of function of NF2.Epigenetic and gene expression alterations in meningioma meningiomas involve restriction landmark genome scan­ Accordingly.68. 2010 Neurosurg Focus / Volume 35 / December 2013 7 .8 A subset of 67 meningiomas showed only   4. Study supervision: Gian­ however. Kaghad M.26 Future Directions Distinction Between Genetic and Epigenetic Mutation The divergence between genetic and epigenetic man­ Targets ifestations in meningioma progression clearly illustrates The most clearly established genetic mutation for me­ the challenge that expression profiles attempt to portray ningiomas is inactivation of the neurofibromin 2 (NF2) in a phenotypically heterogenous neoplasm. In me­ The authors report no conflict of interest concerning the mate­ ningiomas. malignancy in meningiomas. Reifenberger G. 2000 frequency of methylation of CDKN2B (p15[INK4B]). next-generation hypermethylation. On- low unrestrained cell proliferation. disrupt the growth-regulatory pathway and al­ ing and decreased expression of p73 gene in breast cancers: prevalence of alterations in inflammatory breast cancers. 23 with rates ranging from 21% in lung cancers to 34% of all brain tumors. a two-dimensional gel-based method for tion of CDKN transcription in meningiomas might be assessing methylation status in thousands of CpG islands influenced by as yet unknown mechanisms in addition to simultaneously.8   2. then. Pham. alterations in various tumor suppressors are likely to play Zada. This may explain why genetic mecha­ high-throughput techniques for assessing methylation nisms but not epigenetic mechanisms are crucial in me­ status across the entire genome have become increasingly ningioma progression for the RB pathway. Mack. Biochem Cell Biol 74:853–862.

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