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DNA demethylation is associated with malignant progression of lower-grade gliomas

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 recurre...

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Detalles Bibliográficos
Autores principales: 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
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6374451/
https://www.ncbi.nlm.nih.gov/pubmed/30760837
http://dx.doi.org/10.1038/s41598-019-38510-0
Descripción
Sumario: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.