Abstract
Abstract Low-grade glioma, especially astrocytomas often undergo malignant progression, and these transformations are a leading cause of death in patients with low-grade gliomas. However, the mechanisms underlying malignant tumor transformation are still not well understood. Recent evidence indicates that epigenetic deregulation is an important cause of gliomagenesis; therefore, we examined the epigenetic changes during malignant progression of gliomas. We used the Illumina Infinium Human Methylation 450K BeadChip to perform genome-wide DNA methylation analysis of 124 gliomas and four normal brains. These tumors comprised 37 grade IV gliomas, 32 grade III gliomas, and 55 grade II gliomas. This study sample included 26 matched-pairs of initial lower grade gliomas and recurrent tumors and 21 of the 26 recurring tumors recurred as malignant progressions. Analyses of methylation profiles demonstrated that most low-grade gliomas in our sample (84%) had a CpG island methylator phenotype (G-CIMP). Remarkably, approximately 25% of recurrent malignant gliomas that had progressed from low-grade tumors with the G-CIMP status exhibited a characteristic partial demethylation of genomic DNA during malignant progression, but other recurrent gliomas showed no apparent change in DNA methylation pattern. Interestingly, we found that most loci that were demethylated during malignant progression were located outside of CpG islands. The information of histone modifications patterns in normal human astrocytes and embryonal stem cells also showed that the ratio of active marks at the site corresponding to DNA demethylated loci in G-CIMP-demethylated tumors was significantly lower; this finding indicated that most demethylated loci in G-CIMP-demethylated tumors were likely transcriptionally inactive. A small number of the genes that were upregulated and had demethylated CpG islands were associated with cell cycle-related pathway. Here, we demonstrated that partial DNA demethylation occurred during malignant transfomrmation of a subset of lower grade gliomas. Citation Format: Mukasa Akitake, Kuniaki Saito, Koki Aihara, Genta Nagae, Mayu Omata, Ryohei Otani, Shunsaku Takayangi, Shota Tanaka, Yoshitaka Narita, Keisuke Ueki, Ryo Nishikawa, Motoo Nagane, Hiroyuki Aburatani, Nobuhito Saito. DNA methylation profile analysis of gliomas revealed a change in methylation status during malignant progression. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1072. doi:10.1158/1538-7445.AM2015-1072
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