Methylation markers of malignant potential in meningiomas

Laboratory investigation

Restricted access

Object

Although most meningiomas are benign, about 20% are atypical (Grade II or III) and have increased mortality and morbidity. Identifying tumors with greater malignant potential can have significant clinical value. This validated genome-wide methylation study comparing Grade I with Grade II and III meningiomas aims to discover genes that are aberrantly methylated in atypical meningiomas.

Methods

Patients with newly diagnosed meningioma were identified as part of the Ohio Brain Tumor Study. The Infinium HumanMethylation27 BeadChip (Illumina, Inc.) was used to interrogate 27,578 CpG sites in 14,000 genes per sample for a discovery set of 33 samples (3 atypical). To verify the results, the Infinium HumanMethylation450 BeadChip (Illumina, Inc.) was used to interrogate 450,000 cytosines at CpG loci throughout the genome for a verification set containing 7 replicates (3 atypical), as well as 12 independent samples (6 atypical). A nonparametric Wilcoxon exact test was used to test for difference in methylation between benign and atypical meningiomas in both sets. Heat maps were generated for each set. Methylation results were validated for the 2 probes with the largest difference in methylation intensity by performing Western blot analysis on a set of 20 (10 atypical) samples, including 11 replicates.

Results

The discovery array identified 95 probes with differential methylation between benign and atypical meningiomas, creating 2 distinguishable groups corresponding to tumor grade when visually examined on a heat map. The validation array evaluated 87 different probes and showed that 9 probes were differentially methylated. On heat map examination the results of this array also suggested the existence of 2 major groups that corresponded to histological grade. IGF2BP1 and PDCD1, 2 proteins that can increase the malignant potential of tumors, were the 2 probes with the largest difference in intensity, and for both of these the atypical meningiomas had a decreased median production of protein, though this was not statistically significant (p = 0.970 for IGF2BP1 and p = 1 for PDCD1).

Conclusions

A genome-wide methylation analysis of benign and atypical meningiomas identified 9 genes that were reliably differentially methylated, with the strongest difference in IGF2BP1 and PDCD1. The mechanism why increased methylation of these sites is associated with an aggressive phenotype is not evident. Future research may investigate this mechanism, as well as the utility of IGF2BP1 as a marker for pathogenicity in otherwise benign-appearing meningiomas.

Abbreviations used in this paper:OBTS = Ohio Brain Tumor Study; UHCMC = University Hospitals Case Medical Center.
Article Information

Contributor Notes

Address correspondence to: Jill S. Barnholtz-Sloan, Ph.D., Case Comprehensive Cancer Center, CWRU School of Medicine, 11100 Euclid Ave., Wearn 152, Cleveland, OH 44106-5065. email: jsb42@case.edu.Please include this information when citing this paper: published online August 9, 2013; DOI: 10.3171/2013.7.JNS13311.

© AANS, except where prohibited by US copyright law.

Headings
References
  • 1

    Al-Mefty OKadri PAPravdenkova SSawyer JRStangeby CHusain M: Malignant progression in meningioma: documentation of a series and analysis of cytogenetic findings. J Neurosurg 101:2102182004

    • Search Google Scholar
    • Export Citation
  • 2

    Aydemir FYurtcu EBalci TBSahin FIGulsen SAltinors N: Identification of promoter region methylation patterns of MGMT, CDKN2A, GSTP1, and THBS1 genes in intracranial meningioma patients. Genet Test Mol Biomarkers 16:3353402012

    • Search Google Scholar
    • Export Citation
  • 3

    Barski DWolter MReifenberger GRiemenschneider MJ: Hypermethylation and transcriptional downregulation of the TIMP3 gene is associated with allelic loss on 22q12.3 and malignancy in meningiomas. Brain Pathol 20:6236312010

    • Search Google Scholar
    • Export Citation
  • 4

    Bibikova MLin ZZhou LChudin EGarcia EWWu B: High-throughput DNA methylation profiling using universal bead arrays. Genome Res 16:3833932006

    • Search Google Scholar
    • Export Citation
  • 5

    Blank CGajewski TFMackensen A: Interaction of PD-L1 on tumor cells with PD-1 on tumor-specific T cells as a mechanism of immune evasion: implications for tumor immunotherapy. Cancer Immunol Immunother 54:3073142005

    • Search Google Scholar
    • Export Citation
  • 6

    Bock C: Analysing and interpreting DNA methylation data. Nat Rev Genet 13:7057192012

  • 7

    Dolecek TAPropp JMStroup NEKruchko C: CBTRUS statistical report: primary brain and central nervous system tumors diagnosed in the United States in 2005–2009. Neuro Oncol 14:Suppl 5v1v492012

    • Search Google Scholar
    • Export Citation
  • 8

    Drummond KJZhu JJBlack PM: Meningiomas: updating basic science, management, and outcome. Neurologist 10:1131302004

  • 9

    Durand ALabrousse FJouvet ABauchet LKalamaridès MMenei P: WHO grade II and III meningiomas: a study of prognostic factors. J Neurooncol 95:3673752009

    • Search Google Scholar
    • Export Citation
  • 10

    Eichenmüller MGruner IHagl BHäberle BMüller-Höcker Jvon Schweinitz D: Blocking the hedgehog pathway inhibits hepatoblastoma growth. Hepatology 49:4824902009

    • Search Google Scholar
    • Export Citation
  • 11

    Jeffery JMUrquhart AJSubramaniam VNParton RGKhanna KK: Centrobin regulates the assembly of functional mitotic spindles. Oncogene 29:264926582010

    • Search Google Scholar
    • Export Citation
  • 12

    Kai MWang TS: Checkpoint responses to replication stalling: inducing tolerance and preventing mutagenesis. Mutat Res 532:59732003

    • Search Google Scholar
    • Export Citation
  • 13

    Kishida YNatsume AKondo YTakeuchi IAn BOkamoto Y: Epigenetic subclassification of meningiomas based on genome-wide DNA methylation analyses. Carcinogenesis 33:4364412012

    • Search Google Scholar
    • Export Citation
  • 14

    Kline JGajewski TF: Clinical development of mAbs to block the PD1 pathway as an immunotherapy for cancer. Curr Opin Investig Drugs 11:135413592010

    • Search Google Scholar
    • Export Citation
  • 15

    Laird PW: Principles and challenges of genomewide DNA methylation analysis. Nat Rev Genet 11:1912032010

  • 16

    Lemm IRoss J: Regulation of c-myc mRNA decay by translational pausing in a coding region instability determinant. Mol Cell Biol 22:395939692002

    • Search Google Scholar
    • Export Citation
  • 17

    Liu YPang JCDong SMao BPoon WSNg HK: Aberrant CpG island hypermethylation profile is associated with atypical and anaplastic meningiomas. Hum Pathol 36:4164252005

    • Search Google Scholar
    • Export Citation
  • 18

    Lusis EAWatson MAChicoine MRLyman MRoerig PReifenberger G: Integrative genomic analysis identifies NDRG2 as a candidate tumor suppressor gene frequently inactivated in clinically aggressive meningioma. Cancer Res 65:712171262005

    • Search Google Scholar
    • Export Citation
  • 19

    Mawrin CPerry A: Pathological classification and molecular genetics of meningiomas. J Neurooncol 99:3793912010

  • 20

    Meyer LRZweig ASHinrichs ASKarolchik DKuhn RMWong M: The UCSC Genome Browser database: extensions and updates 2013. Nucleic Acids Res 41:D64D692013

    • Search Google Scholar
    • Export Citation
  • 21

    Mojtahedi ZMohmedi MRahimifar SErfani NHosseini SVGhaderi A: Programmed death-1 gene polymorphism (PD-1.5 C/T) is associated with colon cancer. Gene 508:2292322012

    • Search Google Scholar
    • Export Citation
  • 22

    Perry ABanerjee RLohse CMKleinschmidt-DeMasters BKScheithauer BW: A role for chromosome 9p21 deletions in the malignant progression of meningiomas and the prognosis of anaplastic meningiomas. Brain Pathol 12:1831902002

    • Search Google Scholar
    • Export Citation
  • 23

    Perry AStafford SLScheithauer BWSuman VJLohse CM: Meningioma grading: an analysis of histologic parameters. Am J Surg Pathol 21:145514651997

    • Search Google Scholar
    • Export Citation
  • 24

    Shahi MHAfzal MSinha SEberhart CGRey JAFan X: Human hedgehog interacting protein expression and promoter methylation in medulloblastoma cell lines and primary tumor samples. J Neurooncol 103:2872962011

    • Search Google Scholar
    • Export Citation
  • 25

    Shimada HKuboshima MShiratori TNabeya YTakeuchi ATakagi H: Serum anti-myomegalin antibodies in patients with esophageal squamous cell carcinoma. Int J Oncol 30:971032007

    • Search Google Scholar
    • Export Citation
  • 26

    Smith JLKupchak BRGaritaonandia IHoang LKMaina ASRegalla LM: Heterologous expression of human mPRalpha, mPRbeta and mPRgamma in yeast confirms their ability to function as membrane progesterone receptors. Steroids 73:116011732008

    • Search Google Scholar
    • Export Citation
  • 27

    Stöhr NKöhn MLederer MGlass MReinke CSinger RH: IGF2BP1 promotes cell migration by regulating MK5 and PTEN signaling. Genes Dev 26:1761892012

    • Search Google Scholar
    • Export Citation
  • 28

    Tessema MYu YYStidley CAMachida EOSchuebel KEBaylin SB: Concomitant promoter methylation of multiple genes in lung adenocarcinomas from current, former and never smokers. Carcinogenesis 30:113211382009

    • Search Google Scholar
    • Export Citation
  • 29

    Wang WLau RYu DZhu WKorman AWeber J: PD1 blockade reverses the suppression of melanoma antigen-specific CTL by CD4+ CD25(Hi) regulatory T cells. Int Immunol 21:106510772009

    • Search Google Scholar
    • Export Citation
  • 30

    Weidensdorfer DStöhr NBaude ALederer MKöhn MSchierhorn A: Control of c-myc mRNA stability by IGF2BP1-associated cytoplasmic RNPs. RNA 15:1041152009

    • Search Google Scholar
    • Export Citation
  • 31

    Wilkinson KVelloso ERLopes LFLee CAster JCShipp MA: Cloning of the t(1;5)(q23;q33) in a myeloproliferative disorder associated with eosinophilia: involvement of PDGFRB and response to imatinib. Blood 102:418741902003

    • Search Google Scholar
    • Export Citation
  • 32

    Woo SRTurnis MEGoldberg MVBankoti JSelby MNirschl CJ: Immune inhibitory molecules LAG-3 and PD-1 synergistically regulate T-cell function to promote tumoral immune escape. Cancer Res 72:9179272012

    • Search Google Scholar
    • Export Citation
  • 33

    Yisraeli JK: VICKZ proteins: a multi-talented family of regulatory RNA-binding proteins. Biol Cell 97:87962005

TrendMD
Metrics

Metrics

All Time Past Year Past 30 Days
Abstract Views 313 308 77
Full Text Views 171 113 1
PDF Downloads 113 63 0
EPUB Downloads 0 0 0
PubMed
Google Scholar