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Epigenetics. 2018;13(4):432-448. doi: 10.1080/15592294.2018.1469892. Epub 2018 Aug 6.

Genome-wide methylomic and transcriptomic analyses identify subtype-specific epigenetic signatures commonly dysregulated in glioma stem cells and glioblastoma.

Pangeni RP1,2, Zhang Z3,4, Alvarez AA1,2, Wan X1,2, Sastry N1,2,5, Lu S6, Shi T1,2, Huang T1,2, Lei CX1, James CD2,7, Kessler JA1,2, Brennan CW8, Nakano I9, Lu X6, Hu B1,2, Zhang W3,2,4, Cheng SY1,2,4,5.

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a Departments of Neurology, Chicago, IL, USA.
c Lou and Jean Malnati, Brain Tumor Institute & The Robert H. Lurie Comprehensive Cancer Center, Chicago, IL, USA.
b Department of Preventative Medicine, Chicago, IL, USA.
d Driskill Graduate Program in Life Sciences, Chicago, IL, USA.
e Northwestern University Interdepartmental Neuroscience Program , Chicago , IL , USA.
f Department of Biomedical Informatics , University of Pittsburgh , Pittsburgh , PA , USA.
g Department of Neurological Surgery , Northwestern University Feinberg School of Medicine , Chicago , IL , USA.
h Department of Neurosurgery , Memorial Sloan Kettering Cancer Center , NY , NY , USA.
i Department of Neurosurgery , University of Alabama at Birmingham , Birmingham, AL , USA.


Glioma stem cells (GSCs), a subpopulation of tumor cells, contribute to tumor heterogeneity and therapy resistance. Gene expression profiling classified glioblastoma (GBM) and GSCs into four transcriptomically-defined subtypes. Here, we determined the DNA methylation signatures in transcriptomically pre-classified GSC and GBM bulk tumors subtypes. We hypothesized that these DNA methylation signatures correlate with gene expression and are uniquely associated either with only GSCs or only GBM bulk tumors. Additional methylation signatures may be commonly associated with both GSCs and GBM bulk tumors, i.e., common to non-stem-like and stem-like tumor cell populations and correlating with the clinical prognosis of glioma patients. We analyzed Illumina 450K methylation array and expression data from a panel of 23 patient-derived GSCs. We referenced these results with The Cancer Genome Atlas (TCGA) GBM datasets to generate methylomic and transcriptomic signatures for GSCs and GBM bulk tumors of each transcriptomically pre-defined tumor subtype. Survival analyses were carried out for these signature genes using publicly available datasets, including from TCGA. We report that DNA methylation signatures in proneural and mesenchymal tumor subtypes are either unique to GSCs, unique to GBM bulk tumors, or common to both. Further, dysregulated DNA methylation correlates with gene expression and clinical prognoses. Additionally, many previously identified transcriptionally-regulated markers are also dysregulated due to DNA methylation. The subtype-specific DNA methylation signatures described in this study could be useful for refining GBM sub-classification, improving prognostic accuracy, and making therapeutic decisions.


DNA methylation; Glioma stem-like cells (GSC); glioblastoma (GBM); prognostic accuracy; transcriptome signatures

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