ムラガキ　ヨシヒロ   MURAGAKI Yoshihiro   村垣　善浩    所属   医学部 医学科（東京女子医科大学病院）    職種   客員教授
論文種別	原著
言語種別	英語
査読の有無	査読あり
表題	DNA demethylation is associated with malignant progression of lower-grade gliomas.
掲載誌名	正式名：Scientific reports 略　 称：Sci Rep ISSNコード：20452322/20452322
掲載区分	国外
巻・号・頁	9(1),pp.1903
著者・共著者	Nomura Masashi†, Saito Kuniaki, Aihara Koki, Nagae Genta, Yamamoto Shogo, Tatsuno Kenji, Ueda Hiroki, Fukuda Shiro, Umeda Takayoshi, Tanaka Shota, Takayanagi Shunsaku, Otani Ryohei, Nejo Takahide, Hana Taijun, Takahashi Satoshi, Kitagawa Yosuke, Omata Mayu, Higuchi Fumi, Nakamura Taishi, Muragaki Yoshihiro, Narita Yoshitaka, Nagane Motoo, Nishikawa Ryo, Ueki Keisuke, Saito Nobuhito, Aburatani Hiroyuki*, Mukasa Akitake*
発行年月	2019/02
概要	To elucidate the mechanisms of malignant progression of lower-grade glioma, molecular profiling using methylation array, whole-exome sequencing, and RNA sequencing was performed for 122, 36 and 31 gliomas, respectively. This cohort included 24 matched pairs of initial lower-grade gliomas and recurrent tumors, most of which showed malignant progression. Nearly half of IDH-mutant glioblastomas that had progressed from lower-grade gliomas exhibited characteristic partial DNA demethylation in previously methylated genomic regions of their corresponding initial tumors, which had the glioma CpG island methylator phenotype (G-CIMP). In these glioblastomas, cell cycle-related genes, RB and PI3K-AKT pathway genes were frequently altered. Notably, late-replicating domain was significantly enriched in the demethylated regions that were mostly located in non-regulatory regions, suggesting that the loss of DNA methylation during malignant transformation may involve mainly passive demethylation due to a delay in maintenance of methylation during accelerated cell division. Nonetheless, a limited number of genes including IGF2BP3, which potentially drives cell proliferation, were presumed to be upregulated due to demethylation of their promoter. Our data indicated that demethylation of the G-CIMP profile found in a subset of recurrent gliomas reflects accelerated cell divisions accompanied by malignant transformation. Oncogenic genes activated by such epigenetic change represent potential therapeutic targets.
DOI	10.1038/s41598-019-38510-0
PMID	30760837