Study: JGAS00000000146

Identifier

AccessionJGAS00000000146

Description

TitleDNA demethylation is associated with malignant progression of low-grade gliomas
AbstractTo elucidate the mechanisms of tumor progression is key to discovering strategies for treating patients with lower-grade glioma. Thus to characterize the changes in the molecular profile during malignant progression, we performed methylation array analysis (122 tumors), whole-exome sequencing (36 tumors and matched normal samples), and RNA sequencing (31 tumors). This cohort included 24 matched pairs of initial lower-grade gliomas and recurrent tumors, most of which showed malignant progression when they recurred. 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 were upregulated, RB and PI3K-AKT pathway genes were frequently altered. Notably, bioinformatics analysis revealed that 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. Thus, cell proliferation was further promoted by passive demethylation in the promoter region of these oncogenic genes. 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.
Study Type 1
Study TypeTumor vs. Matched-Normal
Study Type 2
Study TypeExome Sequencing
Study Type 3
Study TypeTranscriptome Sequencing
Study Type 4
Study TypeOther
New Study TypeDNA methylation array

Grant

Grant 1
TitleIdentification of new molecular targets with profiling of malignant mesothelioma / Development of therapeutic modalities against intractable cancers via identification of new therapeutic targets with molecular profiling / P-DIRECT: Project for Development of Innovative Research on Cancer Therapeutics
AgencyMinistry of Education, Culture, Sports, Science and Technology (MEXT)
Grant ID
Grant 2
TitleIdentification of new molecular targets with profiling of malignant mesothelioma / Development of therapeutic modalities against intractable cancers via identification of new therapeutic targets with molecular profiling / P-DIRECT: Project for Development of Innovative Research on Cancer Therapeutics
AgencyJapan Agency for Medical Research and Development (AMED)
Grant ID

Study Attribute

NBDC Numberhum0006
Registration date2018-07-25
Submitting organizationDepartment of Neurosurgery, The University of Tokyo
Principal InvestigatorNobuhito Saito
Molecular Data TypeExome sequencing
PlatformHiSeq 2000
VendorIllumina
Comment
Molecular Data TypeTranscriptome profiling by high-throughput sequencing
PlatformHiSeq 2000
VendorIllumina
Comment
Molecular Data TypeMethylation profiling by array
PlatformInfinium HumanMethylation450 BeadChip
VendorIllumina
Comment
Primary PhenotypeGlioma
Cancer TypeGlioma
Dataset
Accession Title Dataset type Data objects Policy
JGAD00000000215 Exome of 36 low-grade gliomas and matched-normal from peripheral blood. Exome sequencing 108 JGAP00000000004
JGAD00000000216 RNAseq of 31 low-grade gliomas. Transcriptome profiling by high-throughput sequencing 62 JGAP00000000004
JGAD00000000217 DNA-methylation array of 113 low-grade gliomas. 0 JGAP00000000004
JGAD00000000218 Exome of 8 pair of primary-recurrent gliomas. Exome sequencing 48 JGAP00000000004
JGAD00000000219 RNAseq of 8 recurrent gliomas. Transcriptome profiling by high-throughput sequencing 16 JGAP00000000004