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Non-promoter hypermethylation of zygote arrest 1 (ZAR1) in human brain tumors

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Zygote arrest 1 (ZAR1) is a novel maternal-effect gene of crucial importance during the oocyte-to-embryo transition. Comprehensive methylation analysis of tumor-specific differently methylated regions in human malignant melanomas has recently led to the identification of non-promoter hypermethylation of the ZAR1 gene that had never been identified as an aberrant methylated region in any human tumor. Notably, ZAR1 hypermethylation was frequently observed in melanomas but was absent in benign nevi, and ZAR1 expression was found to be up-regulated in methylated tumors. These findings prompted us to screen for ZAR1 non-promoter methylation in various types of human brain tumors using MassARRAY EpiTYPER. Strikingly, hypermethylation of ZAR1 was observed frequently in diffuse astrocytomas (100%), anaplastic astrocytomas (94%), glioblastomas (93%), oligodendrogliomas (100%), anaplastic oligodendrogliomas (100%), and pituitary adenomas (90%), but not at all in pilocytic astrocytomas. For other tumor types ZAR1 hypermethylation was infrequent: 17% of vestibular schwannomas and 33% of meningothelial meningiomas. Detectable ZAR1 transcript was not found in any of hypermethylated glioma cell lines. Our results indicate that hypermethylation of the ZAR1 non-promoter is extremely frequent in diffuse gliomas and pituitary adenomas, although ZAR1 expression is unlikely to play a tumorigenic role.

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  1. Mueller W, Nutt CL, Ehrich M et al (2007) Downregulation of RUNX3 and TES by hypermethylation in glioblastoma. Oncogene 26:583–593

    Article  PubMed  CAS  Google Scholar 

  2. Nakamura M, Watanabe T, Klangby U et al (2001) p14 ARF deletion and methylation in genetic pathways to glioblastomas. Brain Pathol 11:159–168

    Article  PubMed  CAS  Google Scholar 

  3. Nakamura M, Yonekawa Y, Kleihues P et al (2001) Promoter hypermethylation of the RB1 gene in glioblastomas. Lab Invest 81:77–82

    PubMed  CAS  Google Scholar 

  4. Nakamura M, Watanabe T, Yonekawa Y et al (2001) Promoter hypermethylation of the DNA repair gene MGMT in astrocytomas is frequently associated with G:C → A:T mutations of the TP53 tumor suppressor gene. Carcinogenesis 22:1715–1719

    Article  PubMed  CAS  Google Scholar 

  5. Ohta T, Watanabe T, Katayama Y et al (2006) Aberrant promoter hypermethylation profile of cell cycle regulatory genes in malignant astrocytomas. Oncol Rep 16:957–963

    PubMed  CAS  Google Scholar 

  6. Watanabe T, Yokoo H, Yokoo M et al (2000) Concurrent inactivation of RB1 and TP53 pathways in anaplastic oligodendrogliomas. J Neuropathol Exp Neurol 60:1181–1189

    Google Scholar 

  7. Watanabe T, Katayama Y, Komine C et al (2005) O 6-Methylguanine-DNA methyltransferase methylation and TP53 mutation in malignant astrocytomas and their relationships with clinical course. Int J Cancer 113:581–587

    Article  PubMed  CAS  Google Scholar 

  8. Ehrich M, Nelson MR, Stanssens P et al (2005) Quantitative high-throughput analysis of DNA methylation patterns by base-specific cleavage and mass spectrometry. Proc Natl Acad Sci USA 102:15785–15790

    Article  PubMed  CAS  Google Scholar 

  9. Shinojima Y, Terui T, Kimura M et al (2010) Identification and analysis of an early diagnostic marker for malignant melanoma: ZAR1 intra-genic differentially methylated region. J Dermatol Sci 59:98–106

    Article  PubMed  CAS  Google Scholar 

  10. Wu X, Viveiros MM, Eppig JJ et al (2003) Zygote arrest 1 (Zar1) is a novel maternal-effect gene critical for the oocyte-to-embryo transition. Nature Genet 33:187–191

    Article  PubMed  CAS  Google Scholar 

  11. Watanabe T, Yachi K, Ohta T et al (2010) Aberrant hypermethylation of non-promoter zygote arrest 1 (ZAR1) in human brain tumors. Neurol Med Chir (Tokyo) 50:1062–1069

    Article  Google Scholar 

  12. Watanabe T, Katayama Y, Yoshino A et al (2007) Aberrant hypermethylation of p14 ARF and O 6-methylguanine-DNA methyltransferase genes in astrocytoma progression. Brain Pathol 17:5–10

    Article  PubMed  CAS  Google Scholar 

  13. Yan H, Parsons W, Jin G et al (2009) IDH1 and IDH2 mutations in gliomas. New Eng J Med 360:765–773

    Article  PubMed  CAS  Google Scholar 

  14. Smith JF, Mahmood S, Song F et al (2007) Identification of DNA methylation in 3′ genomic regions that are associated with upregulation of gene expression in colorectal cancer. Epigenetics 2:161–172

    Article  PubMed  Google Scholar 

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This work was supported in part by Grants-in-Aids for Scientific Research from the Japan Society for the Promotion of Science (grant number 21591883) and the Academic Frontier Project of the 2006 Project for Private Universities, a matching fund subsidy from MEXT (to Hiroki Nagase).

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Correspondence to Takao Watanabe.

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Watanabe, T., Yachi, K., Ohta, T. et al. Non-promoter hypermethylation of zygote arrest 1 (ZAR1) in human brain tumors. Brain Tumor Pathol 28, 199–202 (2011).

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