Epigenetic regulations associated with biological and clinical relevancies in diffuse gliomas

Zygote arrest 1（ZAR 1）是一个新的母源效应基因，在卵母细胞向胚胎转化过程中起着关键作用。最近，对人类恶性黑色素瘤中肿瘤特异性差异甲基化区域的全面甲基化分析鉴定了ZAR 1基因的非启动子超甲基化，该基因从未被鉴定为任何人类肿瘤中的异常甲基化区域。值得注意的是，ZAR 1高甲基化经常在黑色素瘤中观察到，但在良性痣中不存在，并且发现ZAR 1表达在甲基化肿瘤中上调。这些发现促使我们使用MassARRAY EpiTYPER在各种类型的人类脑肿瘤中筛选ZAR 1非启动子甲基化。引人注目的是，在弥漫性星形细胞瘤（100%）、间变性星形细胞瘤（94%）、胶质母细胞瘤（93%）、少突胶质细胞瘤（100%）、间变性少突胶质细胞瘤（100%）和垂体腺瘤（90%）中经常观察到ZAR 1的高甲基化，但在所有毛细胞性星形细胞瘤中均未观察到。其他肿瘤类型显示罕见的ZAR 1高甲基化：17%的前庭神经鞘瘤和33%的脑膜瘤。在高甲基化胶质瘤细胞系中均未检测到ZAR 1转录本。我们的数据表明，ZAR 1非启动子的高甲基化在弥漫性胶质瘤和垂体腺瘤中非常常见，尽管ZAR 1表达不太可能发挥致瘤作用。

Zygote arrest 1(ZAR1) is a novel maternal-effect gene that plays crucial roles during the oocyte-to-embryo transition. Comprehensive methylation analysis of tumor-specific differentially 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 pilocytic astrocytomas. Other tumor types showed infrequent ZAR1 hypermethylation : 17% of vestibular schwannomas and 33% of meningothelial meningiomas. Detectable ZAR1 transcript was not found in any of hypermethylated glioma cell lines. Our data 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.