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Integrative analysis of DNA methylation suggests down-regulation of oncogenic pathways and reduced somatic mutation rates in survival outliers of glioblastoma

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Authors
Hwang, Taeyoung; Mathios, Dimitrios; McDonald, Kerrie L; Daris, Irene; Park, Sung-Hye; Burger, Peter C; Kim, Sojin; Dho, Yun-Sik; Carolyn, Hruban; Bettegowda, Chetan; Shin, Joo Heon; Lim, Michael; Park, Chul-Kee
Issue Date
2019-06-03
Publisher
BioMed Central
Citation
Acta Neuropathologica Communications. 7(1):5
Keywords
GlioblastomaLong-term survivorDNA methylationGenome-wide analyses
Abstract
The study of survival outliers of glioblastoma can provide important clues on gliomagenesis as well as on the ways to alter clinical course of this almost uniformly lethal cancer type. However, there has been little consensus on genetic and epigenetic signatures of the long-term survival outliers of glioblastoma. Although the two classical molecular markers of glioblastoma including isocitrate dehydrogenase 1 or 2 (IDH1/2) mutation and O6-methylguanine DNA methyltransferase (MGMT) promoter methylation are associated with overall survival rate of glioblastoma patients, they are not specific to the survival outliers. In this study, we compared the two groups of survival outliers of glioblastoma with IDH wild-type, consisting of the glioblastoma patients who lived longer than 3 years (n = 17) and the patients who lived less than 1 year (n = 12) in terms of genome-wide DNA methylation profile. Statistical analyses were performed to identify differentially methylated sites between the two groups. Functional implication of DNA methylation patterns specific to long-term survivors of glioblastoma were investigated by comprehensive enrichment analyses with genomic and epigenomic features. We found that the genome of long-term survivors of glioblastoma is differentially methylated relative to short-term survivor patients depending on CpG density: hypermethylation near CpG islands (CGIs) and hypomethylation far from CGIs. Interestingly, these two patterns are associated with distinct oncogenic aspects in gliomagenesis. In the long-term survival glioblastoma-specific sites distant from CGI, somatic mutations of glioblastoma are enriched with higher DNA methylation, suggesting that the hypomethylation in long-term survival glioblastoma can contribute to reduce the rate of somatic mutation. On the other hand, the hypermethylation near CGIs associates with transcriptional downregulation of genes involved in cancer progression pathways. Using independent cohorts of IDH1/2- wild type glioblastoma, we also showed that these two patterns of DNA methylation can be used as molecular markers of long-term survival glioblastoma. Our results provide extended understanding of DNA methylation, especially of DNA hypomethylation, in cancer genome and reveal clinical importance of DNA methylation pattern as prognostic markers of glioblastoma.
ISSN
2051-5960
Language
English
URI
http://hdl.handle.net/10371/156076
DOI
https://doi.org/10.1186/s40478-019-0744-0
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College of Medicine/School of Medicine (의과대학/대학원)Neurosurgery (신경외과학전공)Journal Papers (저널논문_신경외과학전공)
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