title: Aberrant hypermethylation of non-promoter zygote arrest 1 (ZAR1) in human brain tumors.
abstract: Zygote arrest 1 (ZAR1) is a novel maternal-effect gene which is extremely important during the oocyte-to-embryo transition. Comprehensive methylation analysis of tumor-specific differentially methylated regions in human malignant melanoma has recently led to the identification of non-promoter hypermethylation of the ZAR1 gene that had never been previously linked to aberrant methylation. Strikingly, 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. The present study searched for non-promoter ZAR1 hypermethylation in 90 primary human brain tumor samples, normal brain tissue from one autopsy case, and 7 glioma cell lines, employing Sequenom MassARRAY, in which bisulfite-treated fragments are quantitatively detected using time-of-flight mass spectroscopy. ZAR1 transcript expression levels were also evaluated by quantitative real-time reverse transcription-polymerase chain reaction in the 7 glioma cell lines. Hypermethylation of ZAR1 was frequently found in diffuse astrocytomas (7/7, 100%), anaplastic astrocytomas (16/17, 94%), glioblastomas (27/29, 93%), oligodendrogliomas (3/3, 100%), anaplastic oligodendrogliomas (3/3, 100%), and pituitary adenomas (9/10, 90%), but not in pilocytic astrocytomas (0/3). Other tumor types showed infrequent ZAR1 hypermethylation: 1 (17%) of 6 vestibular schwannomas and 4 (33%) of 12 meningothelial meningiomas. The normal brain tissue revealed no evidence of ZAR1 methylation. All 7 glioma cell lines displayed aberrant hypermethylation of ZAR1, but none had detectable ZAR1 transcript. Our findings indicate that non-promoter hypermethylation of ZAR1 is extremely frequent in diffuse gliomas and pituitary adenomas, but methylation-related aberrant ZAR1 expression is far less likely to be related to glioma tumorigenesis.
authors.affiliation: Department of Neurological Surgery, Nihon University School of Medicine, Tokyo, Japan. takao@med.nihon-u.ac.jp
authors.forename: Takao
authors.initials: T
authors.lastname: Watanabe
authors.forename: Kazunari
authors.initials: K
authors.lastname: Yachi
authors.forename: Takashi
authors.initials: T
authors.lastname: Ohta
authors.forename: Takao
authors.initials: T
authors.lastname: Fukushima
authors.forename: Atsuo
authors.initials: A
authors.lastname: Yoshino
authors.forename: Yoichi
authors.initials: Y
authors.lastname: Katayama
authors.forename: Yui
authors.initials: Y
authors.lastname: Shinojima
authors.forename: Tadashi
authors.initials: T
authors.lastname: Terui
authors.forename: Hiroki
authors.initials: H
authors.lastname: Nagase
mesh_terms: D001254:Astrocytoma / Q000378:metabolism / Q000473:pathology; D001921:Brain / Q000378:metabolism*; D001932:Brain Neoplasms / Q000378:metabolism* / Q000473:pathology; D016022:Case-Control Studies; D045744:Cell Line, Tumor; D004527:Egg Proteins / Q000378:metabolism*; D005909:Glioblastoma / Q000378:metabolism / Q000473:pathology; D005910:Glioma / Q000378:metabolism*; D006801:Humans; D013058:Mass Spectrometry; D008545:Melanoma / Q000378:metabolism / Q000473:pathology; D008745:Methylation; D009506:Nevus / Q000378:metabolism / Q000473:pathology; D009837:Oligodendroglioma / Q000378:metabolism / Q000473:pathology; D010911:Pituitary Neoplasms / Q000378:metabolism* / Q000473:pathology; D012016:Reference Values
chemical_list: D004527:Egg Proteins; C471631:Zar1 protein, human