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.
Brain tumor Glioma Mass spectroscopy Methylation Zygote arrest 1
This is a preview of subscription content, log in to check access.
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).
Mueller W, Nutt CL, Ehrich M et al (2007) Downregulation of RUNX3 and TES by hypermethylation in glioblastoma. Oncogene 26:583–593PubMedCrossRefGoogle Scholar
Nakamura M, Watanabe T, Klangby U et al (2001) p14ARF deletion and methylation in genetic pathways to glioblastomas. Brain Pathol 11:159–168PubMedCrossRefGoogle Scholar
Nakamura M, Yonekawa Y, Kleihues P et al (2001) Promoter hypermethylation of the RB1 gene in glioblastomas. Lab Invest 81:77–82PubMedGoogle Scholar
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 22:1715–1719PubMedCrossRefGoogle Scholar
Ohta T, Watanabe T, Katayama Y et al (2006) Aberrant promoter hypermethylation profile of cell cycle regulatory genes in malignant astrocytomas. Oncol Rep 16:957–963PubMedGoogle Scholar
Watanabe T, Yokoo H, Yokoo M et al (2000) Concurrent inactivation of RB1 and TP53 pathways in anaplastic oligodendrogliomas. J Neuropathol Exp Neurol 60:1181–1189Google Scholar
Watanabe T, Katayama Y, Komine C et al (2005) O6-Methylguanine-DNA methyltransferase methylation and TP53 mutation in malignant astrocytomas and their relationships with clinical course. Int J Cancer 113:581–587PubMedCrossRefGoogle Scholar
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 102:15785–15790PubMedCrossRefGoogle Scholar
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 59:98–106PubMedCrossRefGoogle Scholar
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 33:187–191PubMedCrossRefGoogle Scholar
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) 50:1062–1069CrossRefGoogle Scholar
Watanabe T, Katayama Y, Yoshino A et al (2007) Aberrant hypermethylation of p14ARF and O6-methylguanine-DNA methyltransferase genes in astrocytoma progression. Brain Pathol 17:5–10PubMedCrossRefGoogle Scholar
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 2:161–172PubMedCrossRefGoogle Scholar